Abstract
Large-scale cancer genome-sequencing studies have revealed that chromatin regulators are frequently mutated in cancer. In particular, over 20% of cancers harbor mutations in genes that encode subunits of SWI/SNF (BAF) chromatin remodeling complexes. Additional links of SWI/SNF complexes to disease have emerged with the findings that some oncogenes drive transformation by co-opting SWI/SNF function and that germline mutations in select SWI/SNF subunits are the basis of several neurodevelopmental disorders. Other chromatin remodelers, including members of the ISWI, CHD, and INO80/SWR complexes, have also been linked to cancer and developmental disorders. Consequently, therapeutic manipulation of SWI/SNF and other remodeling complexes has become of great interest, and drugs targeting SWI/SNF subunits have entered clinical trials. Genome-wide perturbation screens in cancer cell lines with SWI/SNF mutations have identified additional synthetic lethal targets that have also entered clinical trials, including one that has progressed to FDA approval. Here, we review the progress in understanding the structure and function of SWI/SNF and other chromatin remodeling complexes, mechanisms by which SWI/SNF mutations cause cancer and neurologic diseases, vulnerabilities that arise because of these mutations, and efforts to target SWI/SNF complexes and synthetic lethal targets for therapeutic benefit.
Introduction
Eukaryotic cells require the ability to store large genomes while simultaneously choreographing a myriad of gene expression programs that are lineage-specific and responsive to stimuli. Chromatin was an early evolutionary adaptation that facilitates the compaction, organization, and dynamic regulation of eukaryotic genomes. In humans, two meters of genome is compacted into a 10μm nucleus. The nucleosome is the basic unit of chromatin and consists of 147 base pairs of DNA wrapped around an octamer of four core histones (two each of H2A, H2B, H3, H4). Linker DNA spans between adjacent nucleosomes and is associated with a non-core histone, H1. The extent of chromatin compaction at genes is often associated with their expression level. Highly compacted heterochromatin is inaccessible to transcriptional machinery and tends to be silent, while loosely packed euchromatin is accessible thus enabling controlled activation of gene expression when the relevant transcription factors are present. Chromatin regulators contribute to the control of gene expression through various mechanisms that include mobilizing nucleosomes at regulatory elements and gene bodies, exchanging variants of the core histones, and covalently modifying DNA and histones.
Genetic mutations in chromatin regulators are a frequent contributor to cancer, developmental disorders, and other diseases. In healthy cells, a diverse collection of chromatin regulators cooperates with transcription factors to orchestrate the precise transcriptional control required for development, differentiation, and response to stimuli. Mutations in transcription factors have long been recognized as drivers of cancer with oncogenic consequences resulting from disruption of target pathways that underlie development and signaling. As chromatin regulators cooperate with multiple transcription factors, disruption of these regulators has the potential to perturb multiple transcription factor pathways, potentially explaining the high frequency and diverse manifestations of such mutations in disease.
Chromatin remodelers hydrolyze ATP to reposition nucleosomes on DNA1. In humans, remodelers can be categorized into four main families based on the homology of their ATPase domains: SWI/SNF, ISWI, CHD, and INO80/SWR2. Despite the shared catalytic function of hydrolyzing ATP to remodel chromatin, these complexes incorporate heterogeneous accessory subunits and contribute to diverse functions including regulation of gene expression, 3D chromatin organization, replication, and DNA repair. The regular spacing of nucleosomes is maintained by ISWI and CHD remodelers, while SWI/SNF and INO80/SWIR complexes interrupt this spacing to establish chromatin accessibility by mobilizing nucleosomes or exchanging histone variants, respectively3. The clinical relevance of chromatin remodeling complexes has been increasingly appreciated as mutations in subunits have been identified in cancers, developmental disorders, and other diseases. Genes that encode subunits of SWI/SNF complexes are the most frequently mutated in disease, and therefore these complexes have generated the most pharmacologic interest and are the central focus of this Review. Albeit less frequent, alterations of other complexes are also observed, and interventions are being explored (Box 1)2–7.
Box 1: ISWI, CHD, and INO80 family remodelers.
Mammalian ISWI (Imitation SWI) remodelers are comprised of an ATPase subunit (SMARCA5/SNF2H or SMARCA1/SNF2L) and between one and three non-catalytic accessory subunits that specify functionality263. These heterogeneous complexes have highly context-dependent activity, but generally reposition nucleosomes after replication and maintain fixed spacing of nucleosomes to prevent cryptic transcriptional initiation264. SNF2H also modulates higher-order chromatin structure through associations with CTCF222. Mutations, copy number changes, and altered expression of ISWI ATPases and accessory subunits have recently been observed in cancer, and these perturbations are reported to have tumor-suppressive or oncogenic effects263. However, ISWI complexes are among the least frequently mutated chromatin remodelers in cancer, and no cancers are defined by mutations in ISWI members2. Similarly, ISWI mutations have been detected in some neurodevelopmental disorders, but these mutations are observed in fewer patients than other remodelers (ISWI=1.9%, CHD=2.0%, INO80=3.6%, SWI/SNF=4.1%)10. Nevertheless, initial efforts to develop small molecule inhibitors targeting ISWI ATPases265 and some accessory subunits (CERCR2266, BAZ2A/B267, and BPTF268,269) have begun.
CHD (chromatin helicase DNA-binding) family chromatin remodelers are encoded by 10 genes in humans, which remodel chromatin in distinct ways6. While most CHD remodelers slide nucleosomes (CHD1/2/3/4/7/8/9), others unwrap DNA from nucleosomes without moving them (CHD5/6)270,271. Beyond the heterogeneity of the remodelers themselves, CHD family members are incorporated into diverse multi-subunit complexes with functionally distinct accessory subunits. Such associations facilitate recruitment to regulatory elements, including promoters and enhancers, where they can contribute to the control of transcriptional activation or silencing of their targets6. Perturbations of CHD family members have also been linked to developmental disorders and cancers2,6,10. Some CHD members have been reported to have tumor suppressor activity, including CHD5 haploinsufficiency in neuroblastoma272, and CHD1 in prostate cancers without PTEN deletion273. Curiously, CHD1 becomes essential in PTEN-null prostate cancer274, emphasizing the highly context-dependent role of these remodelers and raising the possibility that CHD1 might be targeted in PTEN-null prostate cancers. Other CHD members have been implicated as having essential roles in additional malignancies, including CHD4 in AML and other cancers275–277, and CHD1L in several solid tumors278. Early small molecule inhibitors of CHD1L have demonstrated efficacy in colorectal cancer cell lines and xenografts279,280, raising the question of whether other CHD remodelers can be therapeutically targeted in disease. Structural studies may provide useful insights to guide drug discovery efforts281.
INO80/SWR (SWI2/SNF2-related) family ATPases include INO80, SMARCAD1, SRCAP, and EP400. Instead of sliding or unwrapping nucleosomes, INO80/SWR family members remodel chromatin by exchanging histone variants within nucleosomes282,283. This interrupts the regular spacing of nucleosomes and generates nucleosome-free regions at transcription start sites284,285. INO80/SWR family mutations are relatively uncommon in cancer2. However, overexpression has been observed in malignancies, and some studies suggest that these remodelers could represent vulnerabilities in transcriptionally-addicted cancers286–288, but may have context-dependent roles289. The EP400/TIP60 complex was recently reported to partially rescue promoter accessibility and transcriptional activation after SWI/SNF inactivation in sensitive cancer cell lines223. Whether this complex can be targeted to improve therapeutic response remains uncertain, but small molecules have been developed against several members of this complex (BRD8290, YEATS4291, and TIP60292).
Genes that encode subunits of SWI/SNF chromatin remodeling complexes are mutated in over 20% of cancers, and increasingly, mutations in SWI/SNF genes are being linked to developmental disorders and other diseases8–10. In cancers without mutations in SWI/SNF subunits, oncogenic transcription factors have been shown to hijack wildtype SWI/SNF complexes to promote transformation11–15. With the growing recognition of the broad links of SWI/SNF complexes to disease, interest in developing targeted therapies is expanding rapidly.
Chromatin regulators exist in complex networks of activators and repressors that cooperate to titrate gene expression. Most disease-associated mutations in SWI/SNF genes appear to impair (but not eliminate) transcriptional activation. In what may be thought of as a Goldilocks phenomenon16,17, CRISPR screens in SWI/SNF-mutant cancer cell lines have demonstrated that these cells can be preferentially sensitive to both the further impairment of SWI/SNF function by targeting other SWI/SNF subunits18–25, and to the rescue of transcriptional activation by inhibiting repressors that oppose SWI/SNF activity26–31 or enhancing SWI/SNF activity32. In the second category, one approach has already progressed to FDA approval: targeted inhibition of Polycomb repressor catalytic subunit EZH2 in cancers mutant for SWI/SNF subunit SMARCB1. This Review will provide a comprehensive overview of opportunities and strategies to target SWI/SNF complexes as well as synthetic lethal targets in SWI/SNF-mutant human cancers. We first describe the structural features of the SWI/SNF complex that facilitate precise chromatin remodeling, as well as the functional consequences of the most frequent disease-associated mutations. Next, we summarize the successes and challenges of treating cancers with SWI/SNF mutations by targeting residual complexes and other synthetic lethalities. We then discuss opportunities to target wildtype SWI/SNF complexes in other diseases. Finally, we conclude with some perspectives for targeting functionally and structurally diverse chromatin regulators relevant to future drug discovery efforts.
SWI/SNF chromatin remodeling complexes
SWI/SNF complexes facilitate transcription
SWI/SNF complexes were first identified in yeast via genetic screens for defective mating-type SWItching (SWI) and sucrose fermentation (Sucrose Non-Fermenting, SNF)33–36. These complexes were then implicated in modulating transcription through chromatin regulation and found to be evolutionarily conserved throughout eukaryotes37. A now well-characterized role of SWI/SNF complexes occurs at non-coding cis-regulatory elements that control the expression of linked genes, including distal enhancers and proximal promoters. Utilizing the energy of ATP hydrolysis, SWI/SNF complexes slide or eject nucleosomes to generate accessibility for sequence-specific transcription factors (TFs) at enhancers and transcriptional machinery at promoters38–42 (Fig 1A). In particular, SWI/SNF has been implicated in the control of genes that are dynamically regulated, including those controlling cell fate during differentiation and in response to environmental signals. In addition to remodeling chromatin at key target genes, SWI/SNF activity is also required to maintain transcriptional memory of cell state by bookmarking lineage-identity genes during cell division43.
Figure 1: Structure and function of SWI/SNF complexes.
A, SWI/SNF complexes localize to enhancers and promoters and hydrolyze ATP to move or eject nucleosomes, generating accessibility for transcription factor (TF) binding. B, The three SWI/SNF subfamilies, canonical BAF (CBAF), polybromo-associated BAF (PBAF), and non-canonical BAF (ncBAF/GBAF), are composed of shared and subfamily-specific subunits. C, Illustration of CBAF, PBAF, and ncBAF/GBAF complexes bound to nucleosomes with subfamily-specific subunits in blue, red, and green, respectively. SMARCA2/4 include catalytic ATPase domains that facilitate remodeling. CBAF and PBAF bilaterally engage nucleosomes through SMARCA2/4 and SMARCB1, but it is not known if ncBAF can bilaterally engage nucleosomes without SMARCB1 as cryo-EM structures of ncBAF have not been reported. SWI/SNF subunits include reader domains, including bromodomains, PHD finger domains, and chromodomains, that can recognize post-translational modifications on histone tails. Flexible features of SWI/SNF complexes and histone tails have not been resolved in existing structural models.
SWI/SNF: SWItch/Sucrose Non-Fermentable; ATP: adenosine triphosphate; ADP: adenosine triphosphate; TF: transcription factor; BAF: BRG-/BRM-associated factor; SMARC: SWI/SNF related, Matrix associated, Actin dependent Regulator of Chromatin; Cryo-EM: cryogenic electron microscopy; PHD: plant homeodomain
The timing of SWI/SNF contributions to transcriptional activation remains an active area of investigation. So-called pioneer transcription factors have demonstrated the capability to bind and activate their targets even in compact heterochromatin areas, and these TFs often recruit SWI/SNF as part of this activation process44–46. In distinction, most canonical TFs preferentially bind to open euchromatin and often depend on SWI/SNF-mediated accessibility to facilitate their binding47,48. A model that fits well with the data is that pioneer TFs recruit SWI/SNF complexes, which in turn open chromatin and facilitate the subsequent binding of other TFs thus resulting in a complex choreography whereby SWI/SNF binding follows the binding of some TFs but precedes the binding of others.
SWI/SNF: complicated complexes
A critical question is how SWI/SNF complexes accomplish the specificity necessary to precisely coordinate such diverse transcriptional states. The compositional diversity of these complexes has increased with organismal complexity across evolution such that twenty-nine genes encode SWI/SNF complex subunits in humans (Table 1). Mammals have three subfamilies of large (~1–2 MDa) SWI/SNF complexes, sometimes referred to as BRG1-associated factors (BAF) complexes, each composed of 8–12 subunits. The three distinct mammalian SWI/SNF subfamilies, termed canonical BAF (CBAF), polybromo-associated BAF (PBAF), and non-canonical BAF (ncBAF or GBAF), consist of both shared subunits and subfamily-specific subunits (Fig 1B, C). Several positions in SWI/SNF complexes can be filled by mutually exclusive paralogues, generating extensive heterogeneity that could theoretically yield over 1,000 combinatorial variants.
Table 1:
Functional domains and organization of SWI/SNF subunits
| Subfamily | Domains* | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| Other Names | CBAF | PBAF | ncBAF | Catalytic | Histone PTM readers | Histone binding | DNA binding | Other | |
| SMARCA4 | BRG1, BAF190A | Y | Y | Y | ATPase, helicase | Bromodomain | SnAC247 | HSA, QLQ | |
| SMARCA2 | BRM, BAF190B, SNF2L2 | Y | Y | Y | ATPase, helicase | Bromodomain | SnAC | HSA, QLQ | |
| SMARCC1 | BAF155 | Y | Y | Y | Chromodomain | SANT, SWIRM | |||
| SMARCC2 | BAF170 | Y | Y | Chromodomain | SANT, SWIRM | ||||
| SMARCB1 | SNF5, BAF47, INI1 | Y | Y | Conserved C-terminal domain248 | Winged helix DNA-binding domain249 | ||||
| SMARCE1 | BAF57 | Y | Y | HMG box | |||||
| SMARCD1 | BAF60A | Y | Y | Y | SWIB | ||||
| SMARCD2 | BAF60B | Y | Y | SWIB | |||||
| SMARCD3 | BAF60C | Y | Y | SWIB | |||||
| ACTB | Y | Y | Y | ||||||
| ACTL6A | BAF53A | Y | Y | Y | Actin-like | ||||
| ACTL6B | BAF53B | Y | Y | Y | Actin-like | ||||
| BCL7A | Y | Y | Y | Conserved N-terminal domain | |||||
| BCL7B | Y | Y | Y | Conserved N-terminal domain | |||||
| BCL7C | Y | Y | Y | Conserved N-terminal domain | |||||
| SS18 | SYT, SSXT | Y | Y | ||||||
| SS18L1 | Y | Y | |||||||
| ARID1A | BAF250A, SMARCF1 | Y | ARID (AT-rich interactive domain) | ||||||
| ARID1B | BAF250B | Y | ARID | ||||||
| DPF1 | BAF45B | Y | PHD finger | ||||||
| DPF2 | BAF45C | Y | PHD finger | ||||||
| DPF3 | BAF45D | Y | PHD finger | ||||||
| ARID2 | BAF200 | Y | ARID, RFX winged helix DBD, zinc finger | ||||||
| PBRM1 | BAF180 | Y | Bromodomains (6) | HMG box | BAH domain | ||||
| BRD7 | Y | Bromodomain | DUF3512 | ||||||
| PHF10 | BAF45A | Y | PHD finger | ||||||
| BRD9 | Y | Bromodomain | DUF3512 | ||||||
| GLTSCR1 | BICRA | Y | |||||||
| GLTSCR1L | BICRAL | Y | |||||||
Selected functionally-relevant domains from annotated domains in Uniprot unless otherwise noted
The function of the paralogues is not entirely interchangeable and, in several cases, has been shown to make differential contributions to lineage specificity. For example, BAF45A and BAF53A are expressed in neural stem cells, while respective paralogs BAF45B/C and BAF53B are expressed in post-mitotic neurons where they serve essential roles in determining cell fate49. The ATPase subunits are also encoded by a pair of paralogs, and they similarly have distinct functions with SMARCA4 critical in early development while SMARCA2 is expressed later50. Differential functions of these subunits are evident in genetically engineered mice, where Smarca4 knockout results in early embryonic lethality, while Smarca2 knockout mice are viable, albeit somewhat larger than normal51. The remarkable combinatorial diversity of SWI/SNF complexes and the tissue-restricted expression of some SWI/SNF subunits raises the possibility that this diversity plays a key role in determining which TFs a complex may interact with and which chromatin landscapes are remodeled50,52–55. Cell state may thus be influenced by the combination of stimuli received, TFs expressed, and composition of SWI/SNF complexes. How the structural heterogeneity of SWI/SNF complexes contributes to functional specificity remains an area of active investigation.
In recent years, structural and biochemical studies have begun to uncover differential functions among the three SWI/SNF subfamilies. The subfamilies preferentially localize to distinct classes of cis-regulatory elements22. CBAF incorporates ARID1A/B and DPF1/2/3 and localizes most strongly to enhancers, while PBAF instead includes ARID2, PBRM1, PHF10, and BRD7 and preferentially localizes to promoters22 (Fig 1B, C). ARID proteins have DNA binding domains and interaction domains with several other subunits of the core module, thus acting as a scaffold that directs CBAF (ARID1A/B) or PBAF (ARID2) complex assembly56. The most recently discovered subfamily, called ncBAF or GBAF, includes neither SMARCB1 nor ARID proteins and instead has GLTSCR1/1L and BRD9. ncBAF localizes to both promoters and distal regulatory elements including enhancers and CTCF sites, suggesting it may also affect the three-dimensional organization of genomes22–24,57. While the three SWI/SNF subfamilies have some distinct characteristics, there is still an incomplete understanding of how the functions of the various subfamilies relate to one another.
Recent cryo-EM structures revealed that SWI/SNF complexes have a modular structure that resembles a C clamp that engages on opposing sides of nucleosomes58–63. The ATPase module includes SMARCA4 (BRG1) or SMARCA2 (BRM), which directly binds the nucleosome and hydrolyzes ATP to generate motion1. The ATPase module is linked by a rigid actin-like ARP module to the chromatin-binding core module58–63. SMARCB1, a subunit in the core module of CBAF and PBAF, forms the other end of the clamp and directly contacts the nucleosome acidic patch through its conserved C-terminal domain64. This bilateral engagement by the ATPase module and SMARCB1 facilitates nucleosome remodeling activity, as perturbations of either nucleosome interaction domain cause defects in remodeling61. Cryo-EM structures of ncBAF have not been published, and whether this SMARCB1-lacking family can similarly engage nucleosomes remains unclear.
Targeting SWI/SNF complexes to chromatin
If the ATPase and ARP modules are the muscle, the core module may act as the brain of the operation by including subunits that can direct remodeling to specific loci. The chromatin binding and genomic localization of SWI/SNF complexes is conferred by subunits with reader domains for histone post-translational modifications (PTMs), subunits that mediate TF interactions, and potentially by subunits that have DNA-binding domains, although the latter are likely sequence non-specific. For example, CBAF-specific subunits DPF2 and DPF3 have tandem PHD finger domains with affinity for acetylated H3K14, found at both promoters and enhancers, but lower affinity for this mark when H3K4me3 is also present, thus contributing to preferential enhancer localization of the CBAF family65,66. Elegant screens measuring the binding and remodeling activity of SWI/SNF complexes on libraries of synthetic nucleosomes revealed that various PTMs can alter the affinity of different SWI/SNF families to chromatin67. This work illustrated that SWI/SNF complexes tend to be attracted to acetylated nucleosomes that mark active chromatin, likely through the numerous bromodomains within SWI/SNF subunits. Repulsion also plays an important role in SWI/SNF complex targeting, as again they observed that CBAF had the lowest affinity towards acetylated nucleosomes that also have H3K4me3, reflecting the enhancer-biased localization of this SWI/SNF subfamily.
SWI/SNF complex localization is influenced by interactions with sequence- and lineage-specific transcription factors, although the structural features of SWI/SNF complexes that mediate interactions with TFs are poorly defined2,15,68. While domains responsible for histone and DNA binding are structured and well-studied, binding to TFs instead seems orchestrated by surfaces of entire SWI/SNF complexes and even by interactions that influence liquid-liquid phase separation (LLPS). LLPS concentrates functionally linked biomolecules (primarily proteins and/or RNA) together in liquid-like, membrane-less condensates through weak, multivalent interactions between intrinsically disordered regions (IDRs) of proteins69. Recent work revealed that IDRs of ARID1A and ARID1B promote LLPS of CBAF complexes and influence interactions with transcription factors and chromatin70. Intriguingly, the IDRs of ARID1A and ARID1B are not functionally interchangeable, and distinct roles in transcriptional regulation have been identified. For example, ARID1B alone facilitates interactions between SWI/SNF complexes and paraspeckles by interacting with the long-non-coding RNA NEAT171. Whether and how other SWI/SNF subunits contribute to interactions with TFs or localization to chromatin through LLPS remains unclear.
SWI/SNF: a common thread in diverse diseases
SWI/SNF mutations are prevalent in cancer
Cancer genome sequencing projects revealed widespread perturbations of chromatin regulators across a broad range of tumor types72,73, to the extent that the propensity of cancer cells to unlock phenotypic plasticity through transcriptional reprogramming is now recognized as a hallmark of cancer74. SWI/SNF complexes are mutated significantly more often than any other chromatin remodeler in cancer, with over 20% of cancers harboring mutations in one or more genes that encode SWI/SNF subunits9,75–78. Indeed, genes encoding at least nine SWI/SNF subunits are recurrently mutated in cancer, with mutations in ARID1A, SMARCA4, PBRM1, and ARID2 among the most common (Fig 2A). These are often nonsense, frameshift, and deletion mutations, suggesting a tumor-suppressor role. Supporting this, genetically engineered mouse models with Smarcb1, Arid1a, Smarca4, or Pbrm1 inactivation are cancer prone38,79–81.
Figure 2: SWI/SNF mutations in cancer.
A, Frequency of mutations in SWI/SNF subunits across all cancers in the TCGA PanCancer Atlas (n=10967). Shared SWI/SNF subunits are shown in gray, and CBAF-, PBAF-, and ncBAF-specific subunits are shown in blue, red, and green, respectively. B, Frequency of mutations in SWI/SNF subunits in select cancers
SWI/SNF: SWItch/Sucrose Non-Fermentable; TCGA: The Cancer Genome Atlas program; SCCOHT: small cell carcinoma of the ovary hypercalcemic type
While the most frequent mutations of SWI/SNF subunits observed in cancer are loss-of-function, the impact on SWI/SNF complexes as a whole is more nuanced. Most of the SWI/SNF genes that are recurrently mutated in cancer are either not present in all three subfamilies or have a paralog, and mounting evidence suggests that these mutations typically do not fully inactivate SWI/SNF function. This is supported by observations that residual SWI/SNF complexes are often essential for the survival of SWI/SNF-mutant cancer cell lines18–25. Further supporting the context specificity of SWI/SNF function, loss-of-function mutations in different SWI/SNF subunits are associated with distinct cancer types (Fig 2B). This suggests that while the individual subunits behave as tumor suppressors, their loss does not have uniform effects on overall SWI/SNF function. Given that mutations in SWI/SNF subunits perturb, rather than inactivate, the collective function of SWI/SNF complexes, the potential for therapeutic targeting of residual complexes is being actively explored both in academia and the commercial sector. With that in mind, it is important to consider the consequences of mutations of different classes of SWI/SNF subunits, as studies have revealed that these can alter diverse aspects of SWI/SNF function, including chromatin targeting and localization, ATP-dependent chromatin remodeling, and complex assembly. Below, we have sorted cancer-associated mutations by their most immediate effect, though they likely influence multiple aspects of SWI/SNF function.
Mutations affecting chromatin binding of SWI/SNF
Pediatric Rhabdoid Tumors (RT) were the first cancer found to be driven by mutation of a gene encoding a SWI/SNF subunit82–84. These highly aggressive cancers occur predominantly in infants and toddlers and carry extremely poor prognoses, with most children succumbing to their disease85,86. SMARCB1 was demonstrated to be a bona fide tumor suppressor when induced somatic inactivation of Smarcb1 in mice was found to rapidly cause cancers in all mice with a median onset of 11 weeks, which is half the time it takes for tumors to form following Tp53 inactivation79. Potentially providing mechanistic clues, the types of cancer resulting from Smarcb1 inactivation in mice are highly specific: typically rhabdoid-like sarcomas and CD8+ T cell lymphomas derived from a memory T cell subset. Unlike p53-mutant cancers, rhabdoid tumors tend to have diploid genomes with extremely few mutations, suggesting that loss of SMARCB1 drives cancer primarily via disruption of transcriptional regulation rather than by causing genome instability87–89. Consistent with this, rescuing SMARCB1 expression in RT cell lines reverses the malignant phenotype and causes cell-cycle arrest90.
Structurally, SMARCB1 binds the acidic patch of nucleosomes on the opposite side from the ATPase subunit (Fig 1C). SMARCB1 loss diminishes chromatin binding and remodeling by CBAF and PBAF subfamilies, leading to destabilization and disposal of residual complexes40. In addition to deletions and frameshift mutations observed in cancer, missense mutations cluster to the C-terminal domain of SMARCB1 that directly contacts the nucleosome, and biochemical assays indicate that these mutations interfere with nucleosome binding and remodeling64. Without SMARCB1, CBAF is unable to maintain accessibility of distal enhancers and levels of other CBAF and PBAF subunits fall39–41. Re-expression of SMARCB1 in rhabdoid tumor cell lines results in the re-accumulation of CBAF and PBAF subfamilies and upregulation of genes associated with differentiation40. Combined with the restricted spectrum of resultant cancer types, this suggests a model whereby SMARCB1 loss, perhaps in a highly proliferative progenitor cell, blocks differentiation and locks the cell into an immature proliferative state. Notably, the level of aggressiveness of cancers caused by such mutations may be a consequence of the cell of origin, as SMARCB1 mutations are observed in both aggressive sarcomas and benign schwannomas91,92. The limited distribution of SMARCB1 aberrations in distinct malignancies suggests that only certain cellular states and developmental intermediates can be transformed by these mutations. Accordingly, the risk of developing rhabdoid tumors decreases greatly in older children, presumably once the susceptible progenitor cells have differentiated85.
Mutations of other SWI/SNF subunits that influence chromatin binding are also implicated in disease. PBRM1, a PBAF-specific subunit, contains six bromodomains that bind to acetylated lysine residues on histone tails and may be important for the engagement of PBAF to chromatin during remodeling93. PBRM1 is mutated in ~40% of clear cell renal carcinomas (ccRCCs), as well as other cancers94,95. Recent work showed that PBRM1 inactivation in ccRCC cell lines causes aberrant localization of residual PBAF complexes, which activates expression programs that drive oncogensis96.
Altered localization of SWI/SNF complexes may also be caused by rarer gain-of-function mutations. BRD9, a bromodomain-containing subunit of ncBAF complexes, is amplified in various cancers including AML and is associated with aberrant enhancer activation97. ACTL6A is amplified or overexpressed in ~25% of all squamous cell carcinomas and leads to the activation of genes necessary for tumor initiation and maintenance by rogue SWI/SNF complexes98. Synovial Sarcoma is a rare soft-tissue tumor that is driven by a chromosomal translocation that fuses an SSX family member to SS18, a subunit of CBAF and ncBAF complexes. The SS18-SSX fusion oncoprotein both prevents SMARCB1 from joining CBAF and causes aberrant localization and remodeling by SWI/SNF complexes99,100.
Another class of mutations that can disrupt SWI/SNF function are mutations in transcription factors, as in several cases these have been shown to drive cancer in part by altering the targeting of wildtype SWI/SNF complexes. Prominent examples include the EWS-FLI1 and TMPRSS2-ERG fusions in Ewing sarcoma and prostate cancer respectively12,13. Diseases driven by such gain-of-function mutations represent strong candidates for drugs that inhibit SWI/SNF complexes.
Mutations affecting catalytic activity of SWI/SNF
SMARCA4 and SMARCA2 are the mutually exclusive catalytic subunits of the SWI/SNF complex that hydrolyze ATP to slide or eject nucleosomes from chromatin. SMARCA4 is mutated in ~4% of all cancers, including breast, lung, and colon cancer, and these mutations are often associated with poor prognoses101–103. Cancer-associated missense mutations of SMARCA4 cluster in the ATPase domain, subunit-subunit interaction interfaces, and nucleosome binding sites, and biochemical studies revealed that these mutations impair enzymatic nucleosome remodeling activity61. In contrast to SMARCA4, SMARCA2 mutations are rarer in cancer, and SMARCA2 tends to be essential for survival in cancer cell lines that lack SMARCA418,20,21. This synthetic lethal relationship has ignited efforts to therapeutically target SMARCA2. However, it is worth noting that not all SMARCA4-mutant cancers rely on the activity of residual SWI/SNF complexes. SMARCA4 is inactivated in nearly all patients with small-cell carcinoma of the ovary hypercalcemic type (SCCOHT) and SMARCA4-deficient thoracic sarcoma104–107, but SMARCA2 is not appreciably expressed in these cancers. Whether the absence of both ATPases is a driving factor in tumorigenesis or reflective of the cell-of-origin has not been determined, but therapeutic strategies must consider such context specificity.
Mutations affecting SWI/SNF composition
Mutations that alter the assembly and composition of SWI/SNF complexes are also prevalent in disease. Mapping of cancer-associated point mutations to cryo-EM structures of human SWI/SNF complexes bound to a nucleosome suggests that only 11% of point mutations directly abrogate catalytic activity61. While another 19% perturb engagement of the nucleosome, the majority of mutations (70%) localize to subunit-subunit interfaces, potentially indicating altered assembly and composition of SWI/SNF complexes as the disease driver. Mutations affecting SWI/SNF subunits that act as the initial scaffolds for assembly of their SWI/SNF complex subfamilies, including ARID1A and ARID2, are among the most frequent in cancer108. ARID1A mutations are found in ~8% of all cancers, including ~45% of ovarian clear cell carcinomas, ~40% of uterine endometrioid cancers, ~30% of gastric cancers, and 10–15% of hepatocellular carcinomas109–114. Establishing its role as a bona fide tumor suppressor, Arid1a inactivation in genetically engineered mice gives rise to colon cancer38. Similar to SMARCB1, ARID1A mutations impair SWI/SNF function at lineage-specific enhancers38, although with a more modest effect perhaps because of compensation from the ARID1B paralog and because ARID1A is only in CBAF complexes, whereas SMARCB1 is in both CBAF and PBAF complexes115. The role of ARID1A in mouse models of hepatocellular carcinoma (HCC) reveals context-specific consequences115,116. Although liver-specific Arid1a knockout delayed tumor initiation in both chemically and genetically induced mouse models, loss of ARID1A in established tumors promoted progression and metastases116.
Structural studies have revealed that ARID1A and ARID1B contain IDRs in their N-termini, followed by DNA-binding domains, and finally interaction domains for several other SWI/SNF subunits in their C-termini. Interestingly, cancer-associated mutations in ARID1A do not cluster to the DNA-binding domain. The high frequency of nonsense and frameshift mutations that leave out the C-terminal protein interaction domains indicate these perturbations affect inter-complex interactions and impair CBAF assembly56. Cancer-associated missense mutations of ARID1A cluster to the N-terminal intrinsically disordered region. These mutations do not affect assembly or remodeling by SWI/SNF complexes, but instead affect liquid-liquid phase separation, interactions with transcription factors, and chromatin localization70. The mutually exclusive paralogue of ARID1A, ARID1B, is less frequently mutated in cancer but has been shown to become preferentially essential in cancer cells that have lost ARID1A function19,117. ARID2, the PBAF-specific relative of ARID1A/B, also acts as a tumor suppressor as it is frequently mutated in hepatocellular carcinoma, non-small cell lung carcinoma, and melanoma118–120. Supporting its essential scaffolding role, ARID2 loss in melanoma interferes with PBAF complex assembly and causes mistargeting of complexes and subsequent activation of genes that facilitate metastases120. Collectively, these findings reveal that disrupting the ordered assembly or composition of SWI/SNF complexes can also drive cancer formation.
SWI/SNF mutations cause developmental disorders
In addition to the somatic mutations that drive cancer, germline mutations in SWI/SNF subunits have more recently been linked to numerous developmental disorders10. These discoveries broaden the link of this family of chromatin regulators to disease and provide further insight into SWI/SNF complex function. The phenotypes are fairly diverse, although most include defects in the nervous system, perhaps reflecting lineage-specific roles of SWI/SNF complexes in controlling gene expression during neural development121, or that changes in brain function may be more likely to come to clinical attention than changes in other organs.
Coffin-Siris syndrome (CSS) and Nicolaides-Baraitser syndrome (NCBRS) are two developmental disorders caused by germline mutations in SWI/SNF subunits121–123. The associated mutations are usually heterozygous, de-novo, and loss-of-function10,123,124. Several SWI/SNF subunits (SMARCA2, SMARCA4, ARID1A, ARID1B, ARID2, SMARCB1, SMARCE1) are implicated in CSS, while NCBRS is associated with mutations in SMARCA2121. Arid1b haploinsufficient mice show phenotypes consistent with CSS, supporting a causative role of SWI/SNF mutations in these diseases125. CSS and NCBRS are clinically characterized by intellectual disability, micro- or macrocephaly, seizures, coarsening of facial features, and abnormalities of the hands and feet, the latter indicating that defects extend beyond neuronal tissues121. Mutations in SWI/SNF subunits have been observed in other neurological and developmental disorders, including Kleefstra’s syndrome (SMARCB1), Hirschsprung’s disease (ARID1B), autism spectrum disorder (SMARCC1, SMARCE1, PBRM1, ARID1B, BCL11A), and schizophrenia (SMARCA2, BCL11A)121. It remains unclear how mutations in identical SWI/SNF subunits can cause distinct developmental disorders, while mutations in different subunits can cause identical disorders.
Individuals with several of these syndromes have developed cancer at an early age, suggesting that the same mutation can both perturb development and promote cancer126. Curiously, the spectrum of mutations most commonly found in cancer differs from those most frequently found in developmental disorders. For instance, ARID1A is mutated much more frequently than ARID1B in cancer. Yet ARID1B mutations are detected nearly four times as often as ARID1A mutations in developmental disorders, and over 70% of patients with Coffin-Siris syndrome harbor a mutation in ARID1B10,123,124. Collectively, these findings suggest that developmental disorders and cancers are related manifestations arising from disrupted roles of SWI/SNF complexes in modulating transcriptional pathways that underlie differentiation and signaling. While driven by mutation of the same complexes that underlie cancer, therapeutic intervention in developmental disorders is likely to be substantially more challenging in part because some physical abnormalities arise during fetal development.
Therapeutic strategies for SWI/SNF mutant cancers
The high prevalence of SWI/SNF mutations in cancer and other diseases prompted the question of whether these mutations create therapeutic vulnerabilities. This is particularly important as most SWI/SNF mutations in cancer are loss-of-function and thus cannot be directly targeted. Yet, with a prevalence of over 20% of all cancers, such mutations have great clinical relevance. Vulnerabilities have now been identified for several types of SWI/SNF mutant cancers and have guided drug discovery efforts and clinical trials (Table 2).
Table 2:
Targeting synthetic lethalities in cancers with mutations in SWI/SNF subunits
| SWI/SNF mutation | Synthetic lethality | Inhibitors | Degraders | Ref | Clinical Trials |
|---|---|---|---|---|---|
| SMARCB1 | BRD9 | I-BRD9#, BI-7271#, BI-7273#, BI-9564# | dBRD9#, CFT-8634~, FHD-609~ | 22,24 |
NCT05355753
NCT04965753 |
| EZH2 | Tazemetostat*, GSK126~ | MS1943# | 27,28 |
NCT01897571
NCT02601950 NCT02601937 NCT03213665 |
|
| DCAF5 | N/A | 32 | |||
| HDAC | Panobinostat* | 157 | NCT04897880 | ||
| MDM2/4 | Idasanutlin~ | 250 | NCT05952687 | ||
| CDK4/6 | Palbociclib*, Abemaciclib*, Ribociclib* | 193 | NCT01747876 | ||
| Aurora A | Tozasertib~, Alisertib~ | JB170#, JB301# | 195 | NCT02114229 | |
| RTK | Lenvatinib*, pazopanib* | 201 | |||
| Ubiquitin-proteosome system | Ixazomib*, bortezomib* | 251 | |||
| Protein translation | Homoharringtonine* | 252 | |||
| SMARCA4 | SMARCA2 | CMP14#, FHT-1015#, FHD-286~ | ACBI1#, ACBI2#, A945#, JQ-dS-4#, SMD-3040#, PRT398~, AU-15330#, AU-24118# | 18,20,21 | NCT05639751 |
| EZH2 | Tazemetostat*, GSK126~ | MS1943# | 28,31 |
NCT01897571
NCT02601950 NCT03213665 |
|
| CDK4/6 | Palbociclib*, Abemaciclib*, Ribociclib* | 190,191 | |||
| Aurora A | Tozasertib~, Alisertib~ | JB170#, JB301# | 196 | ||
| LSD1 | Seclidemstat~ | 253 | NCT04611139 | ||
| Oxidative Phosphorylation | IACS-010759~ | 254 | |||
| BET Bromodomains | JQ1, OTX-015~ | 255 | |||
| SMARCA2 | SMARCA4 | CMP14#, FHT-1015#, FHD-286~ | ACBI1#, JQ-dS-4# | 256 | |
| ARID1A | ARID1B | N/A | 19 | ||
| EZH2 | Tazemetostat*, GSK126~ | MS1943# | 28,29 |
NCT03348631
NCT05023655 |
|
| Aurora A | Tozasertib~, Alisertib~ | JB170#, JB301# | 194 |
NCT01914510
NCT05490472 |
|
| PI3K/AKT | Perifosine~, Buparlisib~, MK-2206~ | 257 | |||
| PARP | Talazoparib*, Olaparib*, Rucaparib*, Veliparib* | 206,258 | NCT05523440 | ||
| ATR | VE-821#, berzosertib~ | 210 |
NCT04065269
NCT03682289 |
||
| HDAC6 | Ricolinostat~ | 259 | NCT05154994 | ||
| LSD1 | Seclidemstat~ | 253 | NCT04611139 | ||
| GCLC | Buthionine sulfoximine~ | 260 | |||
| RTK (Abl, Src, c-KIT) | Dasatinib* | 202 |
NCT04284202
NCT02059265 |
||
| SS18-SSX | BRD9 | I-BRD9#, BI-7271#, BI-7273#, BI-9564# | dBRD9#, CFT-8634~, FHD-609~ | 22,23 |
NCT05355753
NCT04965753 |
| ATR | Berzosertib~, ceralasertib~ | 261 | |||
| KDM2B | N/A | 262 | |||
| PBRM1 | EZH2 | Tazemetostat*, GSK126~ | MS1943# | 28 |
FDA approved drug,
Clinical probe,
Chemical probe.
Some vulnerabilities were identified via traditional hypothesis-driven investigations of SWI/SNF function and included targets such as EZH2. Given the notable complexity of chromatin remodeling and transcriptional regulation, objective large-scale CRISPR inactivation screens were pursued in SWI/SNF-mutant cell lines compared to non-mutant cell lines with a goal of identifying previously unknown mechanisms and dependencies. These latter efforts have indeed yielded both substantial mechanistic insight into SWI/SNF function and revealed numerous unanticipated targetable dependencies127–129. The aforementioned “Goldilocks” phenomenon has emerged whereby cancer-associated mutations in genes that encode SWI/SNF subunits generally reduce but do not fully ablate SWI/SNF activity, leading to conditions that are “just right” for tumorigenesis in certain cellular contexts. Consequently, these cancer cells may be therapeutically targetable either by further impairing the activity of residual SWI/SNF complexes18–25, or by partially rescuing activity by inhibiting chromatin repressors that act antagonistically to SWI/SNF complexes26–31 (Fig 3). Additionally, recent data demonstrate that at least in the case of cancers driven by mutation of SWI/SNF subunit SMARCB1, it may be possible to rescue the function of residual SWI/SNF complexes by targeting protein degradation machinery32. Efforts to target residual SWI/SNF complexes will be discussed first, and other synthetic lethalities will be discussed subsequently.
Figure 3:
Goldilocks phenomenon: Targeting SWI/SNF defects via rescue or further impairment Cancer-associated mutations in SWI/SNF subunits typically impair (but do not outright eliminate) chromatin remodeling and transcriptional activation, leading to a functional profile that is “just right” for tumorigenesis in select cell populations. Studies have revealed that cancer cells with SWI/SNF mutations are sensitive to both rescue or further impairment of chromatin regulation. Chromatin state can be rescued by enhancing the activity of residual complexes or inhibiting antagonistic chromatin regulators, such as the Polycomb Repressive Complex, and often leads to differentiation32,156,157. Chromatin state can be impaired further by targeting residual SWI/SNF complexes, and more frequently leads to cell cycle arrest or cell death20,117.
SWI/SNF: SWItch/Sucrose Non-Fermentable
Targeting residual SWI/SNF complexes
At first pass, it may seem heretical to inhibit complexes for which loss-of-function mutations occur frequently in cancer and developmental disorders. And yet substantial pre-clinical evidence demonstrates that the loss of one SWI/SNF subunit often creates an enhanced dependency on another19–25. Given the specificity of the enhanced dependencies, therapeutic targeting of SWI/SNF complexes has emerged as an active area of investigation both pre-clinically and with several agents now in clinical trials. These agents employ diverse strategies for targeting SWI/SNF activity (Fig 4).
Figure 4:
Strategies to inhibit SWI/SNF complexes A, Small molecules that bind to bromodomains of BRD9 (I-BRD9) and SMARCA2/4 (PFI-3) were developed in an attempt to block chromatin localization of SWI/SNF complexes. These inhibitors were ineffective, presumably because SWI/SNF complexes contain multiple reader domains that remain functional in the presence of the compound. B, Small molecules that inhibit the ATPase activity of SMARCA2/4 (BRM014, FHD-286, FHT-1015) catalytically inactivate SWI/SNF complexes. C, PROTACs that use ligands recognizing bromodomains or ATPase domains degrade SMARCA2, SMARCA4, PBRM1, and BRD9 with varying efficacy to inactivate SWI/SNF complexes. D, Small molecules that block interactions between transcription factors and SWI/SNF complexes have been proposed in cancers driven by oncogenic transcription factors.
*Denotes drugs that are currently in clinical trials.
SWI/SNF: SWItch/Sucrose Non-Fermentable; BRD9: bromodomain-containing protein 9; SMARC: SWI/SNF related, Matrix associated, Actin dependent Regulator of Chromatin; PROTAC: proteolysis targeting chimera; TF: transcription factor
Exploiting Paralogue Dependencies
Two of the SWI/SNF mutations most prevalent in cancer (biallelic loss of SMARCA4 or ARID1A), inactivate one member of a mutually exclusive paralogue pair. Cancer cell lines with these mutations were shown to have specific dependence upon SMARCA2 or ARID1B, respectively, thus raising the prospect of synthetic lethal targeting18–21. Efforts to exploit this type of vulnerability are the furthest advanced for cancers with SMARCA4 mutations. SMARCA4 and SMARCA2 are the mutually exclusive catalytic subunits of SWI/SNF complexes. These proteins both contain bromodomains that tether to acetylated histones and ATPase domains that facilitate the catalytic function of the complex. The discovery that SMARCA2 inactivation damages cancer cells with SMARCA4 mutations but doesn’t seem to impact cells with intact SMARCA4 ignited efforts to target SMARCA2 clinically.
A challenge in therapeutically leveraging these paralogue dependencies has been developing drugs that selectively target one paralogue without affecting the other. In the case of SMARCA2 and SMARCA4, this has proven quite difficult such that clinical exploration initially proceeded with molecules that target both paralogues with the hope that cancer cells mutant for one subunit would display enhanced dependency overall and that toxicity would be acceptable. Early efforts focused on targeting the bromodomains of SMARCA2/4 (PFI-3), but these domains proved to be dispensable for their function, perhaps because other SWI/SNF subunits also contain bromodomains and other reader domains130 (Fig 4A). Efforts then turned to targeting the catalytic ATPase domain of SMARCA2/4 (Fig 4B). Dual-ATPase inhibitors developed by Novartis (BRM014) silenced the expression of SMARCA2 targets and exhibited antiproliferative activity in SMARCA4-mutant cell lines and xenografts, but these drugs were poorly tolerated in preclinical models131. Another small molecule developed by Foghorn Therapeutics (FHT-1015) was also reported to block the ATPase activity of SMARCA2 and SMARCA4 through a distinct mechanism from that of BRM014132. SMARCA2-specific ATPase inhibitors have the potential to exploit this paralogue dependency in SMARCA4 mutant cancers while reducing toxicity, but developing small molecule enzymatic inhibitors that bind only one of the paralogue pair has proven challenging as their ATPase domains are highly homologous (93% conserved).
Subsequently, the advent of targeted protein degradation has enabled previously non-discriminate ligands to be packaged into degraders that have context and kinetic specificity that may allow the targeting of individual paralogues133,134. Contrary to the traditional drug development paradigm that relies on molecules sterically blocking the function of a target protein, PROTACs (proteolysis-targeting chimeras) instead hijack the proteolytic machinery to rapidly and completely degrade target proteins135,136. These heterobifunctional molecules are composed of two linked ligands, with one ligand engaging the target of interest and the other the ubiquitin ligase proteolysis machinery. Tethering a target protein to the proteolytic machinery causes the target to be ubiquitinated and subsequently degraded by the proteasome. This rational approach to designing drugs has yielded rapid progress in targeting SWI/SNF subunits (Fig 4C).
The first SMARCA2/4 PROTAC (ACBI1) used bromodomain ligands to rapidly degrade SMARCA2/4 and PBRM1, another PBAF-specific subunit that shares a similar bromodomain137. PROTACs were later developed that use a ligand that binds to the ATPase domain instead (JQ-dS-4), leaving PBRM1 intact and degrading only SMARCA2 and SMARCA4138. This PROTAC clears its substrates more slowly than bromodomain binders, perhaps because the drug does not displace SMARCA2/4 from chromatin, making them less accessible to E3 ligase machinery. However, neither degrader accomplished specificity for SMARCA2 over SMARCA4.
Generating SMARCA2-specific degraders using bromodomain ligands is still challenging because SMARCA2 and SMARCA4 bromodomains share 96% homology. Next-generation degraders (ACBI2, A947, and SMD-3040) use the same bromodomain-binding ligands that recognize SMARCA2, SMARCA4, and PBRM1, but have attempted to generate specificity to SMARCA2 over SMARCA4 by altering the linker structure139–141. Crystal structures of ternary complexes with SMARCA2 bromodomains, PROTACs, and the recruited E3-ubiquitin ligase informed drug design to distinguish one paralogue from another139,140. ACBI2 and A947 were initially reported to have specificity for degrading SMARCA2 in cell lines and xenografts that lack SMARCA4 and ex vivo in human blood samples. However, these drugs were later found to degrade SMARCA4 and slow the growth of cell lines without SMARCA4 mutations141, raising the possibility of toxicity. The newest iteration, SMD-3040, shows greater selectivity for SMARCA2 and is effective and well-tolerated in preclinical models141. In unpublished data presented at AACR-NCI-EORTC in October 2023, Prelude Therapeutics reported an orally-bioavailable degrader (PRT3798) that shows selectivity towards SMARCA2 in cells and PDX models that express both paralogues and selectivity impairs the growth of tumors with SMARCA4 mutations142. Phase I clinical trials for PRT3798 in SMARCA4-mutant cancers are currently recruiting participants (NCT05639751).
While SMARCA4-mutant cancers currently represent the most actionable paralogue dependency, other cancer-associated SWI/SNF mutations also display similar synthetic lethalities, although drugs are not yet available. ARID1A is the most frequently mutated SWI/SNF subunit in cancer, and ARID1A-mutant cancer cell lines display preferential dependence upon the mutually exclusive paralogue ARID1B for survival19. However, unlike SMARCA2 and SMARCA4, which have ATPase domains and bromodomains, ARID1A and ARID1B lack readily druggable features. High throughput screens identified BD98, a small molecule inhibitor of ARID1A-containing SWI/SNF complexes143. This ligand’s exact mechanism of action is still unknown, but preliminary data suggests that it binds to ARID1A and blocks complex assembly or association with chromatin. These findings suggest that ARID proteins may be targetable, though inhibitors specific to ARID1B are likely to be more clinically relevant. Of note, this synthetic lethal relationship may not extend to all cancers with ARID1A mutations, as liver cancer can still develop in mice when both ARID1A and ARID1B are absent144. This finding reiterates the importance of considering the context specificity of SWI/SNF mutations in tumorigenesis and response to targeted therapies.
Exploiting Non-Paralogue Dependencies
Cancer-associated SWI/SNF mutations can also create non-paralogue dependencies on other SWI/SNF subunits, and drugs targeting this type of synthetic lethality have now entered clinical trials. The most recently discovered SWI/SNF subfamily, ncBAF/GBAF, is currently being pursued as a non-paralogue dependency. ncBAF lacks several subunits common to CBAF and PBAF subfamilies (SMARCB1, SMARCE1, and ARID subunits) and instead includes BRD9 and GLTSCR1/GLTSCR1L. Genome-wide fitness screens and mechanistic studies have revealed preferential dependency of cancer cell lines with select SWI/SNF mutations to BRD9 inactivation22–24. Biallelic SMARCB1 inactivation in pediatric rhabdoid tumors (RT) impairs remodeling by CBAF and PBAF and sensitizes cells to ncBAF inactivation22,24. SMARCE1 inactivation in clear cell meningioma destabilizes CBAF, but not PBAF, and also sensitizes cells to ncBAF inactivation145. Together, this suggests an enhanced role for ncBAF in the maintenance of gene expression when CBAF is dysfunctional. ncBAF has also emerged as a potential target in Synovial Sarcoma, which is driven by an SS18-SSX fusion oncoprotein that incorporates into CBAF and ncBAF complexes and leads to aberrant targeting of SWI/SNF complexes and displacement of SMARCB1 from CBAF complexes22,23,146.
Efforts to target ncBAF initially focused on the bromodomain of BRD9, but early bromodomain ligands (LP99) lacked specificity for BRD9 over the PBAF-specific BRD7147. Bromodomain inhibitors specific to BRD9 (I-BRD9, BI-7271, BI-7273, BI-9564) were developed later but were ineffective in RT cells at clinically relevant doses (Fig 4A)148–150. Similar to the consequences of targeting the bromodomains of SMARCA2/4, these studies found that the BRD9 bromodomain is dispensable for the survival of RT and SS cell lines, perhaps suggesting that SWI/SNF complexes contain a multitude of reader domains that enable them to bind to chromatin when one bromodomain is blocked23. Structure-function studies revealed that RT and SS cells instead depend on the DUF3512 domain that contributes to complex assembly22. Once again, the dawn of targeted protein degradation technology allowed for the recycling of BRD9 bromodomain inhibitors into effective and rapid degraders of BRD9 (dBRD9)151 (Fig 4C). This BRD9 PROTAC showed antiproliferative activity in RT, SS, and CCM cell lines22,23,145. Phase I clinical trials for BRD9 degraders began in patients with cancers driven by SS18-SSX fusion or SMARCB1 inactivation by C4 Therapeutics (CFT-8634, NCT05355753) and Foghorn Therapeutics (FHD-609, NCT04965753). C4 Therapeutics recently announced that their orally available BRD9 degrader was well tolerated and effective at degrading BRD9 in patient tumors, but showed insufficient efficacy in heavily pre-treated patients, and they have thus discontinued the program. The pursuit of BRD9 degraders has also been proposed for other cancers with BRD9 overexpression or amplification, including AML148,152. New compounds with specificity towards BRD7153 (I-78 and 2–77) and PBRM1154,155 (PB16 and GNE-235) have been developed and may have the potential to specifically modulate PBAF activity.
Rescuing transcriptional activation
In contrast to therapeutic strategies that seek to further impair chromatin regulation by targeting residual SWI/SNF complexes, an alternative class of strategies seeks to rescue transcriptional activation by targeting antagonistic chromatin repressors or by enhancing remodeling by residual complexes (Fig 3). This often leads to cell cycle arrest and differentiation, potentially suggesting a rescue of lineage-specific gene expression32,156,157.
Targeting Antagonistic Chromatin Regulators
SWI/SNF complexes were initially found to act antagonistically to Polycomb repressive complexes in genetic screens performed in Drosophila158–160. In humans, the Polycomb Repressive Complex 2 (PRC2) is composed of a methyltransferase, EZH2 or EZH1, and several accessory subunits including EED, SUZ12, and RBBP4/7 that collectively tri-methylate H3K27 to silence and compact chromatin at regulatory elements. In opposition to this, SWI/SNF complexes mobilize nucleosomes and recruit acetyltransferases including P300 that acetylate H3K27 to open and activate chromatin41.
Upon the initial discovery that mutation of SMARCB1 was the basis of an aggressive type of childhood cancer, the earlier finding from Drosophila that Polycomb opposes SWI/SNF activity led to the question of whether unchecked silencing by Polycomb contributes to the genesis or survival of cancers driven by SWI/SNF mutations. Rhabdoid tumors (RT) have proven a particularly powerful model since these highly aggressive and lethal cancers appear to be driven by mutation of a single SWI/SNF subunit (SMARCB1) in the context of a simple diploid genome. Additionally, the role of SMARCB1 as a tumor suppressor has been validated by genetically engineered mouse models79.
Early work found that PRC2 aberrantly silences the expression of tumor suppressors in SMARCB1-mutant RT cells26. Upon SMARCB1 loss, PRC2 indeed re-localizes to sites usually bound by SWI/SNF complexes and writes the repressive H3K27me3 modification to silence gene expression27. This effect is strongest at enhancers, which are significantly impaired by SMARCB1 loss in RT cells41. RT cell lines were sensitive to EZH2 knockdown, but the most compelling evidence supporting this synthetic lethality was that genetically engineered mouse models with conditional Smarcb1 and Ezh2 knockout completely blocked the rapid tumor onset driven by Smarcb1 loss alone27. Notably, dependence upon EZH2 derives from both catalytic and non-catalytic activities of EZH228,161. Cancer cell lines with mutations in other SWI/SNF subunits, including ARID1A, PBRM1, and SMARCA4, also displayed relative sensitivity to Polycomb inactivation28–31. Later mechanistic studies revealed that SWI/SNF activity is sufficient to block Polycomb from silencing chromatin, as artificial recruitment of SWI/SNF complexes rapidly evicts Polycomb complexes from regulatory elements such as enhancers and prevents silencing162.
Following the development of the first small-molecule methyltransferase inhibitors of EZH2156,163–166, testing began in SWI/SNF mutant cancers. Tazemetostat (EPZ-6438) encouragingly reduced methylation of H3K27 and was shown to halt the growth of RT cell lines and xenografts156. In line with a mechanism where inhibiting Polycomb reverses silencing of lineage-specific gene expression, cell cycle arrest and evidence of differentiation were observed in RT cells treated with tazemetostat156. Phase I/II clinical trials of tazemetostat in patients with relapsed or refractory B-cell non-Hodgkin lymphoma or advanced solid tumors, including 13 patients with SMARCB1 or SMARCA4 mutations, showed tolerability and reduction of H3K27me3 in a dose-dependent manner (NCT01897571)167. Several patients in this trial with SMARCB1-mutant tumors met response criteria: one patient with RT showed a complete response, and two with epithelioid sarcoma showed prolonged stable disease. The drug was then tested in patients with soft tissue sarcomas characterized by SWI/SNF mutations or EZH2 gain of function mutations (NCT02601950). Tazemetostat demonstrated the greatest efficacy in advanced SMARCB1-mutant epithelioid sarcoma, with an overall response rate of 15%, including 8/62 patients having a partial response and 2/43 patients having a full response168. This antitumor activity appeared to be durable, as 67% of responding patients had a response lasting 6 months or longer. Though infrequent, the durable responses of patients with this rare and advanced disease who lacked treatment options were compelling and, in January 2020, led to the FDA approval of tazemetostat for patients 16 years and older with metastatic or locally advanced epithelioid sarcoma not eligible for complete resection.
However, tazemetostat as an enzymatic inhibitor showed limited success in other cancers with SWI/SNF mutations. Phase I trials in pediatric patients with SMARCB1-deficient cancers showed a 17% response rate, with one patient developing secondary malignancy (NCT02601937)169. Tazemetostat was used tumor-agnostically in pediatric patients with deleterious mutations in SMARCA4 or SMARCB1 or gain of function mutations in EZH2 as a part of the NCI-Pediatric MATCH program (NCT03213665)170,171. The drug was well tolerated, but response rates were low and variable between cancers with identical genetic perturbations. The overall response for rhabdoid tumors in the central nervous system (5/21, 24%) was higher than that of RT in other tissues (0/21, 0%)170,171. Trials for tazemetostat in ARID1A-mutant cancers are also ongoing (NCT03348631).
Given the strong genetic evidence of enhanced dependence of SWI/SNF-mutant cancers upon EZH2, including current data from the Cancer Dependency Map, it is important to ask why clinical responses to EZH2 inhibitors have not been more robust. Several possibilities exist. As participants in early-phase clinical trials have often been treated with prior regimens, relevant resistance mutations may have emerged172,173. The higher response rate of CNS RT compared to RT in other tissues could have occurred because the dose utilized for non-CNS tumors (520mg/m2) was less than half of the dose used for CNS tumors (1200mg/m2)170. Thus, there is substantial interest in pursuing a trial in which the higher dose regimen is utilized for patients with non-CNS RT. Although RTs are genetically similar, their variable responses to EZH2 inhibitors could be influenced by the distinct cells of origin and epigenetic subclasses these tumors fall into174. Dual inhibitors targeting EZH2 and its paralogue EZH1 were proposed after EZH1 upregulation was observed in RT cells treated with EZH2 inhibitors, but cancer cell lines with SWI/SNF mutations were not found to be broadly sensitive to one such dual inhibitor175–177. Finally, it has been shown that the preferential dependence of SWI/SNF mutant cancers upon EZH2 is derived from both enzymatic and non-enzymatic roles of EZH228,178–180. As an enzymatic inhibitor, it is possible that tazemetostat is not sufficient and that a degrader may be more effective. Degraders targeting EZH2 alone or multiple members of PRC2 have been developed181–186. Encouragingly, cancer cell lines and xenografts that are sensitive to EZH2 knockout, but not EZH2 inhibitors, appear to be sensitive to one EZH2 degrader (MS1943)181. These findings highlight an important concept where enzymatically inhibiting one member of a complex may not be equivalent to inhibiting the entire complex.
In addition to Polycomb, other repressive chromatin regulators have been explored as potential targets in SWI/SNF mutant cancer. Acetylated histone post-translational modifications such as H3K27ac are present at active regulatory elements, including enhancers and promoters. In addition to maintaining the accessibility of these sites, SWI/SNF complexes also recruit P300, the acetyltransferase that writes H3K27ac41. Since the histone deacetylases (HDACs) that erase this PTM are often overexpressed in SWI/SNF mutant cancer, inhibiting HDACs has been explored. Low doses of Panobinostat, a pan-HDAC inhibitor, were found to restore H3K27 acetylation and trigger differentiation of SMARCB1-mutant RT cells157. This finding is the basis of ongoing phase II clinical trials of pan-HDAC inhibitors in pediatric RT patients (NCT04897880)187. However, pan-HDAC inhibitors tend to have broad toxicities, so the pursuit of more specific HDAC inhibitors is underway.
Enhancing remodeling by residual complexes
A recent finding revealed that at least in the case of cancers mutant for SWI/SNF subunit SMARCB1, substantial restoration of SWI/SNF function that effectively reverses the cancer state may be possible32. The absence of SMARCB1 has been shown to impair SWI/SNF complex integrity and lead to reduced protein levels of several SWI/SNF subunits40. Genome-wide CRISPR screens identified the little-studied gene DCAF5 as a specific dependency in RT cell lines32. Dependency upon DCAF5 for survival was unique to SMARCB1-deficient cell lines and was not seen in other SWI/SNF mutant cancers. Mechanistically, it was shown that DCAF5 functions as a quality control factor and the absence of SMARCB1 triggers DCAF5 to degrade residual SWI/SNF complexes. Upon DCAF5 degradation, residual SWI/SNF complexes accumulate on chromatin. Despite the absence of SMARCB1, these complexes had sufficient function to fully reverse the cancer state, ultimately leading to differentiation phenotypes that resemble those observed after SMARCB1 rescue. Thus, cancer results not from the loss of SMARCB1 function per se, but rather from DCAF5-mediated degradation of residual SWI/SNF complexes. Encouragingly, DCAF5 inactivation led to a complete response in xenograft models of rhabdoid tumors. Notably, genetically engineered mice with germline knockout of DCAF5 were viable and indistinguishable from littermate controls through the study limit of 12 weeks of age, suggesting that while targeting DCAF5 may have profound negative effects upon SMARCB1-deficient cancer cells it may have minimal effect upon normal cells and tissues. Cryo-EM structures of DCAF5 were determined as part of this study and can inform future drug discovery efforts. Collectively, these data indicate that therapeutic targeting of ubiquitin-mediated quality control factors may effectively reverse the malignant state of some cancers driven by disruption of tumor suppressor complexes. Whether targeted inhibition of any of the other 20+ DCAF proteins in the genome may be beneficial for other SWI/SNF mutant cancers or cancers driven by other tumor suppressors remains to be determined.
Beyond chromatin: targeting other synthetic lethalities
Large-scale genetic and pharmacological screens of hundreds of cancer cell lines have identified other vulnerabilities created by mutations in SWI/SNF members (Table 2). These systematic screens have identified novel synthetic lethalities, revealed unanticipated mechanisms, and allowed for the repurposing of existing drugs in patients with SWI/SNF mutations. Synthetic lethalities revealed by these efforts have been described elsewhere8,188,189. Select vignettes that highlight novel strategies entering the clinic and important insights revealed by such screening efforts are described below. While these efforts have identified cancer-specific dependencies, general vulnerabilities that would apply universally to all SWI/SNF-mutant cancers remain elusive.
The early discovery of oncogenic kinases resulted in numerous FDA-approved kinase inhibitors. Pharmacological screens have revealed that some kinase inhibitors may be selectively effective in cancers with SWI/SNF mutations. Cell cycle kinases represent one such vulnerability, and drugs targeting the G1/S and G2/M transition have progressed into clinical trials in patients harboring mutations in SWI/SNF subunits. SMARCA4-mutant non-small cell lung cancers and SCCOHT were found to be sensitive to CDK4/6 inhibitors that block the G1/S transition, presumably because residual SWI/SNF complexes can only maintain low levels of cyclin D1 expression that is essential for tumorogenesis190,191. Indeed, limited chromatin accessibility is observed at the CCND1 gene and at its upstream activator JUN in these cells190,191. Phase I trials of CDK4/6 inhibitors led to stable disease in some patients with SMARCB1 mutations (NCT01747876)192,193. Mutations in SMARCB1, SMARCA4, and ARID1A also sensitize cancer cells to Aurora A kinase (AURKA) inhibitors that block the G2/M transition194–196. Similarly, this susceptibility is thought to arise from insufficient expression of AURKA caused by SWI/SNF loss197. However, phase II trials of these enzymatic inhibitors of AURKA in patients with ARID1A or SMARCB1 mutations showed limited efficacy (NCT01914510, NCT02114229)198,199. Recently, PROTAC-mediated degradation of AURKA revealed non-enzymatic roles in replication that are not inactivated by enzymatic inhibitors alone200, raising the question of whether degraders may be more efficacious.
Screening efforts also revealed that cancer cell lines with ARID1A, SMARCA4, and SMARCB1 mutations are sensitive to broad-spectrum receptor tyrosine kinase inhibitors (TKIs)201–203. Notably, as a group, these cancers did not appear to be sensitive to the genetic inactivation of any single receptor tyrosine kinase. Perhaps the cell-of-origin influences which receptor tyrosine kinase is the most important. Nevertheless, the action of these broad-spectrum TKIs is being further investigated. Dasatinib was found to arrest ARID1A-mutant ovarian cancer cells in G1 and encouraging responses in pre-clinical xenograft models have led to phase II trials of dasatinib in ARID1A mutant cancers (NCT04284202, NCT02059265). While the mechanism underlying the sensitivity of SWI/SNF mutant cancers to TKIs remains elusive, this insight will be valuable as SWI/SNF inhibitors are explored in combination therapies to increase the efficacy of TKIs used to treat EGFR-mutant lung cancers204.
Synthetic lethal relationships to inhibitors of DNA repair pathways have also been described for some SWI/SNF-mutant cancers. In addition to facilitating chromatin accessibility at transcriptional regulatory elements, SWI/SNF complexes have been shown to remodel chromatin around sites of DNA damage to prime for repair205, and several SWI/SNF subunits have been implicated in DNA repair pathways, including ARID1A115,206, SMARCA4207, and PBRM1208. Vulnerabilities to PARP and ATR inhibitors have been reported in cancers with mutations in ARID1A mutations209,210, and these are now being investigated in several clinical trials (Table 2). Observations that cancers driven by germline mutations in SWI/SNF subunits tend to have simple genomes with few mutations, have a rapid onset, and are highly lineage-restricted suggest that the tumor-promoting effects of SWI/SNF mutations may principally derive from impaired transcriptional regulation rather than from disrupted DNA repair87,105–107. For example, germline mutation of SMARCB1 results in the rapid and fully penetrant formation of lineage-restricted cancers that have diploid genomes and extremely low mutation rates. Re-expression of SMARCB1 in RT models causes the cells to differentiate, consistent with the absence of SMARCB1 driving cancer by causing a differentiation block. Separately, patients who have germline mutations in SMARCA4 develop early-onset of a specific subtype of ovarian cancer that also have simple genomes with low mutation burden. Additionally, there is a notable lineage bias in the type of cancer that forms depending upon which SWI/SNF subunit is mutated seemingly consistent with differential effects upon lineage-specific transcription programs. Regardless of the mechanism that causes SWI/SNF mutations to promote cancer, these mutations may have effects on DNA repair and result in clinically relevant synthetic vulnerabilities with DNA repair machinery. Additionally, while PARP is often described in the context of DNA repair, it also has roles in transcriptional regulation making it an interesting question whether defective transcription also contributes to the vulnerability of SWI/SNF mutant cancers to PARP inhibition211.
Targeting wildtype SWI/SNF complexes in cancer
Beyond cancers with mutations in SWI/SNF subunits, recent studies have identified preferential dependencies upon SWI/SNF complexes in transcriptionally dysregulated cancers driven by fusion oncoproteins12,13,212,213, TF amplification11,14,15,214,215, or mutations in histone genes216,217, and in cancers prone to develop resistance to targeted therapies204. Unlike efforts to leverage paralogue dependencies in cancers with SMARCA4 mutations by developing inhibitors capable of binding only SMARCA2, these scenarios likely require dual ATPase inhibitors, which are easier to develop. These potential therapeutic opportunities have driven efforts to improve the bioavailability and reduce the toxicity of SWI/SNF-targeting drugs.
Targeting transcriptionally dysregulated cancers
Transcriptional reprogramming and phenotypic plasticity are now recognized as hallmarks of cancer74, and the propensity for cancers to become “addicted” to certain transcriptional states has been well described218. In these cancers, oncogenic gene expression programs are driven by transcription factors that become aberrantly active through amplification, overexpression caused by enhancer hijacking or other mechanisms, or chromosomal re-arrangements. The resulting transcriptional defects can block differentiation to keep cells in a proliferative state, reverse differentiation, or cause trans-differentiation. Efforts to directly target the driving TFs have been challenging as TFs typically lack druggable features219. Thus, targeting cofactors recruited by these oncogenic TFs by using inhibitors of chromatin regulators, including SWI/SNF, is also being explored.
These transcriptionally dysregulated cancers may be sensitized to SWI/SNF inhibitors in two ways. First, it has long been appreciated that TFs recruit SWI/SNF as a coactivator of transcription, and there is now compelling evidence that several oncogenic TFs depend on the recruitment of SWI/SNF complexes for gene activation12–15. This suggests that inhibiting SWI/SNF could block oncogenic TFs from activating gene expression. Second, many of these TFs promote their own expression and the mRNAs encoding these TFs and the TF proteins themselves often have exceptionally short half-lives218. Consequently, these programs have been identified as preferentially dependent upon SWI/SNF. As one example, transcription factor-addicted prostate cancer cells driven by AR and FOXA1 activation are selectively sensitive to a novel dual SWI/SNF ATPase degrader (AU-15330)14. Another strong proof of principle for inhibiting SWI/SNF in transcriptionally dysregulated cancers has unfolded in AML driven by MYC amplification. Initial studies found that SWI/SNF activity is necessary for high levels of MYC expression and leukemia maintenance in cell and mouse models of AML11,55. Later work revealed that another transcription factor, PU.1, recruits SWI/SNF to the super-enhancer of MYC to drive its overexpression220. Supporting these mechanistic findings, dual SMARCA2/4 ATPase inhibitors were found to display enhanced activity in AML cells215.
However, translating these findings to the clinic has not been straightforward. Dual ATPase inhibitors from Foghorn Therapeutics recently entered phase I clinical trials in patients with relapsed/refractory AML and MDS (FHD-286, NCT04891757), but a hold was placed on this trial after patients developed toxicity potentially consistent with differentiation syndrome. Subsequent studies in PDX models published in a preprint suggest that FHD-286 causes differentiation of AML cells and prolonged survival of mice without significant weight loss221. In-depth toxicological analyses of FHD-286 in essential organs have not been reported in preclinical models, but this preprint did describe reductions in platelet counts that resolved after treatment ended. Ultimately, data supporting that the toxicity in the AML trial was due to on-target differentiation syndrome resulted in the FDA lifting the hold on the trial. Although increased dependency on SWI/SNF has been demonstrated in several TF-addicted models, comprehensive analyses of toxicological outcomes in preclinical models and patients will be critical to understanding the safety profile of these SWI/SNF inhibitors given that TFs in normal cells also rely on SWI/SNF activity. Encouragingly, PDX models treated with AU-15330 experienced tumor regression without evidence of toxicity in essential organs or significant weight loss14, and an orally bioavailable derivative of this degrader (AU-24118) also showed antitumor activity in mice again without evidence of toxicity in a recent preprint213.
Given the increased dependency on SWI/SNF in cancers with signature mutations driving transcriptional dysregulation, understanding the mechanisms that underlie sensitivity, resistance, and toxicity to SWI/SNF inhibition has become an active area of investigation. A study in mouse embryonic stem cells (mESCs) found that some TFs, including CTCF, are unaffected by SWI/SNF inactivation and instead rely on ISWI remodeling complexes for binding, suggesting that SWI/SNF inhibition may not be universally effective in TF-driven cancers222. Another study found that EP400, an INO80/SWR family remodeler, partially rescued chromatin accessibility at some promoters after SWI/SNF inactivation and that molecular genomic analysis could accurately predict gene sensitivity to SWI/SNF inhibition in diverse cancer cell lines223. These findings are advancing the understanding of mechanisms that may determine response and toxicity to SWI/SNF inhibitors and thus provide guidance to the clinical advancement of drugs targeting SWI/SNF.
Beyond inhibiting the enzymatic activity of SWI/SNF complexes, other strategies being explored to block transcriptional activation by SWI/SNF include leveraging structural insights to identify surfaces of SWI/SNF complexes that bind to oncogenic TFs, with a goal of disrupting these interactions and potentially reducing off-target toxicities (Fig 4D). In an April 2023 presentation at Drug Discovery Chemistry, Foghorn Therapeutics reported unpublished data identifying an interface between PU.1 and SWI/SNF that could influence MYC overexpression in AML and proposed developing small molecule inhibitors of this interaction224. The heterogeneity of SWI/SNF complex composition and diversity of the TF milieu could conceivably yield strong context specificity to such an approach, the understanding of which will benefit from further structural, mechanistic, and empirical investigation.
Preventing resistance to existing targeted therapies
Targeted therapies have transformed treatment for some cancers, but acquired resistance can render these drugs ineffective. As resistance can be acquired through epigenetic alterations, interest has arisen in targeting chromatin regulators in combination therapies225. The SWI/SNF complex was recently identified as a compelling candidate in EGFR-mutant lung cancers treated with tyrosine kinase inhibitors (TKIs)204. These inhibitors target activating mutations of EGFR found in 15–50% of lung adenocarcinomas, but resistance to this targeted therapy is common and often cannot be explained by additional mutations of EGFR226. This study found that the SWI/SNF complex is essential for the fate switch that allows these tumors to survive in the presence of TKIs, and further that some of these tumors can be re-sensitized via pharmacological inhibition of SWI/SNF204. Future studies will be needed to determine the extent to which SWI/SNF inhibitors can be utilized in combination to prevent tolerance to targeted therapies, as drugs that target other chromatin regulators have shown promising preclinical results in preventing resistance to standard chemotherapy227,228.
Targeting SWI/SNF in non-cancerous cells
Enhancing the efficiency of immunotherapy
Advances in immunotherapy allow the retraining of immune cells using drugs or direct manipulation to target and destroy cancer cells. In CAR-T therapy, T cells are modified with a chimeric antigen receptor to target them to kill cancer cells. However, sustained antigen stimulation from exposure to high cancer burden can cause CAR-T cells to become exhausted and dysfunctional, which in turn impairs their activity229. Epigenetic changes have been noted to accompany the fate switch that leads to T-cell exhaustion230–232, and efforts to circumvent exhaustion by targeting regulators of DNA methylation have improved persistence and antitumor activity in mouse models and in patients233,234. However, recent studies found that genetically inactivating TET2 in CAR-T cells can cause hyperproliferation and genomic instability, thus illuminating risks associated with permanently inactivating epigenetic regulators in cell-based therapy235. CRISPR screens revealed that SWI/SNF is essential in the epigenetic switch that transitions effector T-cells into their exhausted state233,234. Transiently treating CAR-T cells with CBAF inhibitors (BD98), SMARCA2/4 ATPase inhibitors (FHT-1015, BRM014), or SMARCA2/4 degraders (ACBI1, AU-15330) during activation in the manufacturing process proved sufficient to improve their persistence and antitumor activity long-term in mouse models236,237. These findings suggest that treating CAR-T cells with SWI/SNF inhibitors during activation could be explored further as a potentially cheaper and safer alternative for improving CAR-T persistence and antitumor activity. Additionally, recent studies identifying SWI/SNF complexes as critical regulators of the proliferation, differentiation, and function of unmodified T cells raised the possibility that targeting SWI/SNF could also be clinically valuable to enhance response to immune checkpoint inhibitors237–239.
Targeting SWI/SNF in infectious diseases
Though SWI/SNF inhibition has primarily been explored in the context of cancer, recent studies have identified SWI/SNF as a potential target for the treatment of some infectious diseases. CRISPR screens identified SWI/SNF members as essential for SARS-CoV-2 infection, and subsequent studies found that treating cells with SWI/SNF ATPase inhibitors can block SARS-CoV-2 infection240,241. Further, CBAF was shown to be critical for maintaining latency in HIV-1 infected cells, and CBAF-specific inhibitors reversed latency and sensitized these cells to anti-retroviral therapy143. Though no SWI/SNF inhibitors have been advanced clinically to treat infectious diseases, this represents a novel area of investigation.
Concluding remarks
Given the core role that disruption of chromatin regulation and transcription factor function have in driving myriad cancers, there is intense interest in therapeutic manipulation of chromatin regulators in pursuit of targeted response. As the most frequently mutated chromatin remodeler, SWI/SNF complexes have been of particular interest. Insights into aberrant SWI/SNF function have revealed novel vulnerabilities that have guided drug development efforts, yielding early signs of efficacy including an FDA approval.
In cancers with mutations in SWI/SNF subunits, a frequent theme has emerged where reduced, but not eliminated, remodeling by SWI/SNF complexes can drive disease in highly specific cellular conditions. Novel therapeutic strategies seek to leverage this “Goldilocks” phenomenon in SWI/SNF mutant cancers by either further impairing chromatin regulation by inhibiting residual SWI/SNF complexes or by rescuing activation by targeting repressors that oppose SWI/SNF function or by enhancing the activity of residual complexes. Understanding what makes cellular conditions optimal for transformation by SWI/SNF mutations remains an area of active investigation, as this context specificity likely influences the response to drugs targeting chromatin regulators. Perhaps the chromatin landscape in cells is a better predictor for response to therapy than simply mutational status. Defining the chromatin landscape of cell lines included in genetic and pharmacologic screens may be valuable in understanding susceptibility and enhancing accuracy in predicting response.
Enzymatic inhibition has often been considered synonymous with inactivation, as enzymatic inhibitors that target oncogenic kinases such as BCR-ABL1 and Ras have shown remarkable success in the clinic. However, chromatin remodelers are large multi-subunit complexes, and some vulnerabilities revealed by genetic screens are not fully recapitulated by enzymatic inhibition alone. Given the recent recognition that SWI/SNF, Polycomb, and other chromatin regulators undergo liquid-liquid phase separation, this additional layer of biochemical function should be considered along with the well-defined non-enzymatic roles of subunits in the assembly and localization of complexes. Drugs that degrade subunits, disrupt complex assembly, or interfere with TF binding may thus be of great interest for targeting these large multifaceted complexes, along with emerging efforts to develop drugs that alter condensate formation69. However, toxicity remains a major obstacle to targeting SWI/SNF clinically because although some cancers are selectively sensitive to SWI/SNF inactivation, SWI/SNF is still an important regulator in healthy cells.
PROTACs and degraders have recently emerged as powerful tools to target SWI/SNF complexes. Exciting progress has been made in developing SMARCA2/4 degraders, but the specificity towards SMARCA2 over SMARCA4 may still need to be improved to leverage paralogue dependencies and reduce toxicity in cancers with SMARCA4 mutations. The efficacy of PROTACs is in part determined by the abundance of the E3 ubiquitin ligase receptor that is recruited to degrade the targets, so targeting niche E3 ligase receptors that are enriched in tumors could promote tumor-specific degradation of targets135. The bioavailability of PROTACs is still a major bottleneck in drug discovery. Though these catalytic drugs can be used at low dosages because they are recycled, getting these large molecules into cells remains challenging, especially to treat cancers of the central nervous system where they must penetrate the blood-brain barrier. While molecular glues are smaller than PROTACs and have improved bioavailability, the well-recognized challenges of designing these molecules would be amplified by the heterogeneity and structural complexity of SWI/SNF complexes135. Whether antibody-degrader conjugates can improve the bioavailability and tissue-specific activity of PROTACs is also being investigated242. However, relevant targets that lack druggable pockets and have highly homologous paralogues remain untargetable, such as ARID1B in cancers with ARID1A mutations. Recent studies of nanobody-based degraders showed promising results for degrading proteins with highly similar paralogues that lack targetable domains, specifically BCL11A but not BCL11B, within intact cells243,244.
It will also be important to investigate mechanisms of resistance to SWI/SNF inhibition to inform combination therapies. Some TFs recruit other remodeling complexes to generate accessibility222, and recent work showed that an INO80/SWR family remodeler (EP400) can compensate for SWI/SNF inactivation at promoters in cancer cells treated with dual ATPase inhibitors and degraders223. Though in their infancy, efforts to target other chromatin remodeling complexes could be valuable in these situations and warrant further exploration. Finally, inactivation may not represent the sole strategy to chemically manipulate chromatin regulators to modify transcription in disease. The recent innovation of a novel class of bivalent small molecules that can direct the localization of regulators to specific sites on chromatin (TCIPs: transcriptional/epigenetic chemical inducers of proximity) may unlock new modalities to target chromatin remodeling complexes to modulate transcription for therapeutic benefit245,246.
Further drug discovery efforts utilizing novel and creative strategies to target these multi-subunit chromatin complexes, complemented by structural and mechanistic studies, have the potential to both yield functional insight and enhance therapeutic responses for a wide variety of cancers and other diseases.
Acknowledgments
The authors thank the National Cancer Institute (NCI) for their funding support (R01 CA113794, R01 CA172152, and R01 CA273455 to C.W.M.R). The work of C.W.M.R. is also supported by the American Lebanese Syrian Associated Charities (ALSAC) of St. Jude Children’s Research Hospital (SJCRH), including funding from the St. Jude Children’s Research Hospital Collaborative Research Consortium on Chromatin Regulation in Pediatric Cancer, and grants from Cure AT/RT Now, the Avalanna Fund, and the Garrett B. Smith Foundation. H. A. M. is supported by the St. Jude Graduate School of Biomedical Sciences and the Ruth L. Kirschstein National Research Service Award (F31 CA278355). The authors thank members of the Roberts lab, Adam Durbin (SJCRH), and Elizabeth Wickman (SJCRH) for insightful discussions and Vani Shanker (SJCRH) for scientific editing of the manuscript.
Footnotes
Competing interests
C.W.M.R. is a scientific advisory board (SAB) member of Exo Therapeutics, unrelated to this manuscript.
References
- 1.Narlikar GJ, Sundaramoorthy R & Owen-Hughes T Mechanisms and functions of ATP-dependent chromatin-remodeling enzymes. Cell 154, 490–503, doi: 10.1016/j.cell.2013.07.011 (2013). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Gourisankar S, Krokhotin A, Wenderski W & Crabtree GR Context-specific functions of chromatin remodellers in development and disease. Nat Rev Genet, doi: 10.1038/s41576-023-00666-x (2023). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Clapier CR Sophisticated Conversations between Chromatin and Chromatin Remodelers, and Dissonances in Cancer. International Journal of Molecular Sciences 22 (2021). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Reyes AA, Marcum RD & He Y Structure and Function of Chromatin Remodelers. Journal of Molecular Biology 433, 166929, doi: 10.1016/j.jmb.2021.166929 (2021). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Hota SK & Bruneau BG ATP-dependent chromatin remodeling during mammalian development. Development 143, 2882–2897, doi: 10.1242/dev.128892 (2016). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Alendar A & Berns A Sentinels of chromatin: chromodomain helicase DNA-binding proteins in development and disease. Genes Dev 35, 1403–1430, doi: 10.1101/gad.348897.121 (2021). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Eustermann S, Patel AB, Hopfner K-P, He Y & Korber P Energy-driven genome regulation by ATP-dependent chromatin remodellers. Nature Reviews Molecular Cell Biology, doi: 10.1038/s41580-023-00683-y (2023). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Mittal P & Roberts CWM. The SWI/SNF complex in cancer — biology, biomarkers and therapy. Nature Reviews Clinical Oncology 17, 435–448, doi: 10.1038/s41571-020-0357-3 (2020). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. Kadoch C et al. Proteomic and bioinformatic analysis of mammalian SWI/SNF complexes identifies extensive roles in human malignancy. Nat Genet 45, 592–601, doi: 10.1038/ng.2628 (2013). Early and robust analysis of SWI/SNF complex mutations in cancer genome sequencing studies.
- 10. Valencia AM et al. Landscape of mSWI/SNF chromatin remodeling complex perturbations in neurodevelopmental disorders. Nat Genet, doi: 10.1038/s41588-023-01451-6 (2023). Comprehensive guide to SWI/SNF complex mutations in neurodevelopmental disorders.
- 11. Shi J et al. Role of SWI/SNF in acute leukemia maintenance and enhancer-mediated Myc regulation. Genes Dev 27, 2648–2662, doi: 10.1101/gad.232710.113 (2013). An early study highlighting the essential role of SWI/SNF complexes in gene activation by oncogenic TFs.
- 12. Boulay G et al. Cancer-Specific Retargeting of BAF Complexes by a Prion-like Domain. Cell 171, 163–178.e119, doi: 10.1016/j.cell.2017.07.036 (2017). Discovered that wildtype SWI/SNF complexes can be hijacked by fusion oncoproteins and may represent clinically actionable targets in these cancers.
- 13.Sandoval GJ et al. Binding of TMPRSS2-ERG to BAF Chromatin Remodeling Complexes Mediates Prostate Oncogenesis. Mol Cell 71, 554–566.e557, doi: 10.1016/j.molcel.2018.06.040 (2018). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. Xiao L et al. Targeting SWI/SNF ATPases in enhancer-addicted prostate cancer. Nature 601, 434–439, doi: 10.1038/s41586-021-04246-z (2022). An elegant demonstration of how targeting SWI/SNF complexes collapses oncogenic transcriptional circuits in transcriptionally dysregulated cancers.
- 15.Takaku M et al. GATA3-dependent cellular reprogramming requires activation-domain dependent recruitment of a chromatin remodeler. Genome Biology 17, 36, doi: 10.1186/s13059-016-0897-0 (2016). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Tian L et al. Long-read sequencing unveils IGH-DUX4 translocation into the silenced IGH allele in B-cell acute lymphoblastic leukemia. Nature Communications 10, 2789, doi: 10.1038/s41467-019-10637-8 (2019). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Seong BKA et al. TRIM8 modulates the EWS/FLI oncoprotein to promote survival in Ewing sarcoma. Cancer Cell 39, 1262–1278.e1267, doi: 10.1016/j.ccell.2021.07.003 (2021). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Oike T et al. A Synthetic Lethality–Based Strategy to Treat Cancers Harboring a Genetic Deficiency in the Chromatin Remodeling Factor BRG1. Cancer Research 73, 5508–5518, doi: 10.1158/0008-5472.CAN-12-4593 (2013). [DOI] [PubMed] [Google Scholar]
- 19.Helming KC et al. ARID1B is a specific vulnerability in ARID1A-mutant cancers. Nat Med 20, 251–254, doi: 10.1038/nm.3480 (2014). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Hoffman GR et al. Functional epigenetics approach identifies BRM/SMARCA2 as a critical synthetic lethal target in BRG1-deficient cancers. Proc Natl Acad Sci U S A 111, 3128–3133, doi: 10.1073/pnas.1316793111 (2014). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Wilson BG et al. Residual complexes containing SMARCA2 (BRM) underlie the oncogenic drive of SMARCA4 (BRG1) mutation. Mol Cell Biol 34, 1136–1144, doi: 10.1128/mcb.01372-13 (2014). Demonstrates that cancers with mutations in one mutually exclusive SWI/SNF subunit can create an enhanced dependency upon another, which led to efforts to target these “paralogue dependencies” clinically.
- 22.Michel BC et al. A non-canonical SWI/SNF complex is a synthetic lethal target in cancers driven by BAF complex perturbation. Nat Cell Biol 20, 1410–1420, doi: 10.1038/s41556-018-0221-1 (2018). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Brien GL et al. Targeted degradation of BRD9 reverses oncogenic gene expression in synovial sarcoma. eLife 7, e41305, doi: 10.7554/eLife.41305 (2018). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Wang X et al. BRD9 defines a SWI/SNF sub-complex and constitutes a specific vulnerability in malignant rhabdoid tumors. Nat Commun 10, 1881, doi: 10.1038/s41467-019-09891-7 (2019). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Schick S et al. Systematic characterization of BAF mutations provides insights into intracomplex synthetic lethalities in human cancers. Nat Genet 51, 1399–1410, doi: 10.1038/s41588-019-0477-9 (2019). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Kia SK, Gorski MM, Giannakopoulos S & Verrijzer CP SWI/SNF mediates polycomb eviction and epigenetic reprogramming of the INK4b-ARF-INK4a locus. Mol Cell Biol 28, 3457–3464, doi: 10.1128/mcb.02019-07 (2008). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27. Wilson BG et al. Epigenetic antagonism between polycomb and SWI/SNF complexes during oncogenic transformation. Cancer Cell 18, 316–328, doi: 10.1016/j.ccr.2010.09.006 (2010). Identifies Polycomb repressive complexes as a synthetic lethal target in cancers with SWI/SNF mutations that led to the clinical advancement and, ultimately, FDA approval of EZH2 inhibitors in one SWI/SNF mutant cancer.
- 28.Kim KH et al. SWI/SNF-mutant cancers depend on catalytic and non-catalytic activity of EZH2. Nat Med 21, 1491–1496, doi: 10.1038/nm.3968 (2015). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Bitler BG et al. Synthetic lethality by targeting EZH2 methyltransferase activity in ARID1A-mutated cancers. Nat Med 21, 231–238, doi: 10.1038/nm.3799 (2015). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Kawano S et al. Preclinical Evidence of Anti-Tumor Activity Induced by EZH2 Inhibition in Human Models of Synovial Sarcoma. PLoS One 11, e0158888, doi: 10.1371/journal.pone.0158888 (2016). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Chan-Penebre E et al. Selective Killing of SMARCA2- and SMARCA4-deficient Small Cell Carcinoma of the Ovary, Hypercalcemic Type Cells by Inhibition of EZH2: In Vitro and In Vivo Preclinical Models. Molecular Cancer Therapeutics 16, 850–860, doi: 10.1158/1535-7163.MCT-16-0678 (2017). [DOI] [PubMed] [Google Scholar]
- 32. Radko-Juettner S et al. Targeting DCAF5 suppresses SMARCB1-mutant cancer via stabilizing SWI/SNF. Nature In Press (2024). Reveals that function of SMARCB1-deficient SWI/SNF complexes can be substantially rescued by targeting a ubiquitin ligase quality control factor that degrades SWI/SNF complexes in the absence of SMARCB1.
- 33.Neigeborn L & Carlson M GENES AFFECTING THE REGULATION OF SUC2 GENE EXPRESSION BY GLUCOSE REPRESSION IN SACCHAROMYCES CEREVISIAE. Genetics 108, 845–858, doi: 10.1093/genetics/108.4.845 (1984). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Peterson CL & Herskowitz I Characterization of the yeast SWI1, SWI2, and SWI3 genes, which encode a global activator of transcription. Cell 68, 573–583, doi: 10.1016/0092-8674(92)90192-f (1992). [DOI] [PubMed] [Google Scholar]
- 35.Cairns BR, Kim YJ, Sayre MH, Laurent BC & Kornberg RD A multisubunit complex containing the SWI1/ADR6, SWI2/SNF2, SWI3, SNF5, and SNF6 gene products isolated from yeast. Proc Natl Acad Sci U S A 91, 1950–1954, doi: 10.1073/pnas.91.5.1950 (1994). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Martens JA, Wu PY & Winston F Regulation of an intergenic transcript controls adjacent gene transcription in Saccharomyces cerevisiae. Genes Dev 19, 2695–2704, doi: 10.1101/gad.1367605 (2005). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Hernandez-Garcia J et al. Comprehensive identification of SWI/SNF complex subunits underpins deep eukaryotic ancestry and reveals new plant components. Commun Biol 5, 549, doi: 10.1038/s42003-022-03490-x (2022). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Mathur R et al. ARID1A loss impairs enhancer-mediated gene regulation and drives colon cancer in mice. Nat Genet 49, 296–302, doi: 10.1038/ng.3744 (2017). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Nakayama RT et al. SMARCB1 is required for widespread BAF complex-mediated activation of enhancers and bivalent promoters. Nat Genet 49, 1613–1623, doi: 10.1038/ng.3958 (2017). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Wang X et al. SMARCB1-mediated SWI/SNF complex function is essential for enhancer regulation. Nat Genet 49, 289–295, doi: 10.1038/ng.3746 (2017). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41.Alver BH et al. The SWI/SNF chromatin remodelling complex is required for maintenance of lineage specific enhancers. Nat Commun 8, 14648, doi: 10.1038/ncomms14648 (2017). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42.Tolstorukov MY et al. Swi/Snf chromatin remodeling/tumor suppressor complex establishes nucleosome occupancy at target promoters. Proc Natl Acad Sci U S A 110, 10165–10170, doi: 10.1073/pnas.1302209110 (2013). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 43.Zhu Z et al. Mitotic bookmarking by SWI/SNF subunits. Nature 618, 180–187, doi: 10.1038/s41586-023-06085-6 (2023). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44.Singhal N et al. Chromatin-Remodeling Components of the BAF Complex Facilitate Reprogramming. Cell 141, 943–955, doi: 10.1016/j.cell.2010.04.037 (2010). [DOI] [PubMed] [Google Scholar]
- 45.Wolf BK et al. Cooperation of chromatin remodeling SWI/SNF complex and pioneer factor AP-1 shapes 3D enhancer landscapes. Nat Struct Mol Biol, doi: 10.1038/s41594-022-00880-x (2022). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 46.Frederick MA et al. A pioneer factor locally opens compacted chromatin to enable targeted ATP-dependent nucleosome remodeling. Nat Struct Mol Biol, doi: 10.1038/s41594-022-00886-5 (2022). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 47.Schick S et al. Acute BAF perturbation causes immediate changes in chromatin accessibility. Nat Genet 53, 269–278, doi: 10.1038/s41588-021-00777-3 (2021). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 48.Iurlaro M et al. Mammalian SWI/SNF continuously restores local accessibility to chromatin. Nat Genet 53, 279–287, doi: 10.1038/s41588-020-00768-w (2021). [DOI] [PubMed] [Google Scholar]
- 49.Lessard J et al. An essential switch in subunit composition of a chromatin remodeling complex during neural development. Neuron 55, 201–215, doi: 10.1016/j.neuron.2007.06.019 (2007). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 50.Ho L et al. An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency. Proc Natl Acad Sci U S A 106, 5181–5186, doi: 10.1073/pnas.0812889106 (2009). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 51.Bultman S et al. A Brg1 null mutation in the mouse reveals functional differences among mammalian SWI/SNF complexes. Mol Cell 6, 1287–1295, doi: 10.1016/s1097-2765(00)00127-1 (2000). [DOI] [PubMed] [Google Scholar]
- 52.de la Serna IL, Carlson KA & Imbalzano AN Mammalian SWI/SNF complexes promote MyoD-mediated muscle differentiation. Nat Genet 27, 187–190, doi: 10.1038/84826 (2001). [DOI] [PubMed] [Google Scholar]
- 53.Lickert H et al. Baf60c is essential for function of BAF chromatin remodelling complexes in heart development. Nature 432, 107–112, doi: 10.1038/nature03071 (2004). [DOI] [PubMed] [Google Scholar]
- 54.Olave I, Wang W, Xue Y, Kuo A & Crabtree GR Identification of a polymorphic, neuron-specific chromatin remodeling complex. Genes Dev 16, 2509–2517, doi: 10.1101/gad.992102 (2002). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 55.Buscarlet M et al. Essential role of BRG, the ATPase subunit of BAF chromatin remodeling complexes, in leukemia maintenance. Blood 123, 1720–1728, doi: 10.1182/blood-2013-02-483495 (2014). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 56. Mashtalir N et al. Modular Organization and Assembly of SWI/SNF Family Chromatin Remodeling Complexes. Cell, doi: 10.1016/j.cell.2018.09.032 (2018). An elegant study that outlines how the three distinct SWI/SNF subfamilies are assembled.
- 57.Alpsoy A & Dykhuizen EC Glioma tumor suppressor candidate region gene 1 (GLTSCR1) and its paralog GLTSCR1-like form SWI/SNF chromatin remodeling subcomplexes. Journal of Biological Chemistry 293, 3892–3903, doi: 10.1074/jbc.RA117.001065 (2018). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 58.Wagner FR et al. Structure of SWI/SNF chromatin remodeller RSC bound to a nucleosome. Nature 579, 448–451, doi: 10.1038/s41586-020-2088-0 (2020). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 59.Shuang He ZW, Yuan Tian, Zishuo Yu, Jiali Yu, Xinxin Wang, Jie Li, Bijun Liu and Yanhui Xu. Structure of nucleosome-bound human BAF complex. Science 367, 875–881, doi: 10.1126/science.aaz9761 (2020). [DOI] [PubMed] [Google Scholar]
- 60.Han Y, Reyes AA, Malik S & He Y Cryo-EM structure of SWI/SNF complex bound to a nucleosome. Nature 579, 452–455, doi: 10.1038/s41586-020-2087-1 (2020). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 61. Mashtalir N et al. A Structural Model of the Endogenous Human BAF Complex Informs Disease Mechanisms. Cell 183, 802–817 e824, doi: 10.1016/j.cell.2020.09.051 (2020). In-depth, structurally-informed analysis of SWI/SNF mutations found in disease.
- 62.Yuan J, Chen K, Zhang W & Chen Z Structure of human chromatin-remodelling PBAF complex bound to a nucleosome. Nature, doi: 10.1038/s41586-022-04658-5 (2022). [DOI] [PubMed] [Google Scholar]
- 63.Wang L et al. Structure of nucleosome-bound human PBAF complex. Nat Commun 13, 7644, doi: 10.1038/s41467-022-34859-5 (2022). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 64.Valencia AM et al. Recurrent SMARCB1 Mutations Reveal a Nucleosome Acidic Patch Interaction Site That Potentiates mSWI/SNF Complex Chromatin Remodeling. Cell 179, 1342–1356.e1323, doi: 10.1016/j.cell.2019.10.044 (2019). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 65.Zeng L et al. Mechanism and regulation of acetylated histone binding by the tandem PHD finger of DPF3b. Nature 466, 258–262, doi: 10.1038/nature09139 (2010). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 66.Local A et al. Identification of H3K4me1-associated proteins at mammalian enhancers. Nature Genetics 50, 73–82, doi: 10.1038/s41588-017-0015-6 (2018). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 67.Mashtalir N et al. Chromatin landscape signals differentially dictate the activities of mSWI/SNF family complexes. Science 373, 306–315, doi: 10.1126/science.abf8705 (2021). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 68.Esch D et al. A unique Oct4 interface is crucial for reprogramming to pluripotency. Nature Cell Biology 15, 295–301, doi: 10.1038/ncb2680 (2013). [DOI] [PubMed] [Google Scholar]
- 69.Mitrea DM, Mittasch M, Gomes BF, Klein IA & Murcko MA Modulating biomolecular condensates: a novel approach to drug discovery. Nature Reviews Drug Discovery 21, 841–862, doi: 10.1038/s41573-022-00505-4 (2022). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 70.Patil A et al. A disordered region controls cBAF activity via condensation and partner recruitment. Cell, doi: 10.1016/j.cell.2023.08.032 (2023). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 71.Reddy D et al. Paraspeckles interact with SWI/SNF subunit ARID1B to regulate transcription and splicing. EMBO reports 24, e55345, doi: 10.15252/embr.202255345 (2023). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 72.Shen H & Laird, Peter W. Interplay between the Cancer Genome and Epigenome. Cell 153, 38–55, doi: 10.1016/j.cell.2013.03.008 (2013). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 73.Garraway Levi A. & Lander, Eric S. Lessons from the Cancer Genome. Cell 153, 17–37, doi: 10.1016/j.cell.2013.03.002 (2013). [DOI] [PubMed] [Google Scholar]
- 74.Hanahan D Hallmarks of Cancer: New Dimensions. Cancer Discov 12, 31–46, doi: 10.1158/2159-8290.CD-21-1059 (2022). [DOI] [PubMed] [Google Scholar]
- 75.Bailey MH et al. Comprehensive Characterization of Cancer Driver Genes and Mutations. Cell 173, 371–385.e318, doi: 10.1016/j.cell.2018.02.060 (2018). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 76.Tate JG et al. COSMIC: the Catalogue Of Somatic Mutations In Cancer. Nucleic Acids Res 47, D941–d947, doi: 10.1093/nar/gky1015 (2019). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 77.Zehir A et al. Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat Med 23, 703–713, doi: 10.1038/nm.4333 (2017). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 78.Shain AH & Pollack JR The spectrum of SWI/SNF mutations, ubiquitous in human cancers. PLoS One 8, e55119, doi: 10.1371/journal.pone.0055119 (2013). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 79.Roberts CW, Leroux MM, Fleming MD & Orkin SH Highly penetrant, rapid tumorigenesis through conditional inversion of the tumor suppressor gene Snf5. Cancer Cell 2, 415–425, doi: 10.1016/s1535-6108(02)00185-x (2002). [DOI] [PubMed] [Google Scholar]
- 80.Bultman SJ et al. Characterization of mammary tumors from Brg1 heterozygous mice. Oncogene 27, 460–468, doi: 10.1038/sj.onc.1210664 (2008). [DOI] [PubMed] [Google Scholar]
- 81.Gu YF et al. Modeling Renal Cell Carcinoma in Mice: Bap1 and Pbrm1 Inactivation Drive Tumor Grade. Cancer Discov 7, 900–917, doi: 10.1158/2159-8290.Cd-17-0292 (2017). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 82. Versteege I et al. Truncating mutations of hSNF5/INI1 in aggressive paediatric cancer. Nature 394, 203–206, doi: 10.1038/28212 (1998). Initial identification of a mutation in a chromatin remodeling complex as a cancer driver.
- 83.Biegel JA et al. Germ-line and acquired mutations of INI1 in atypical teratoid and rhabdoid tumors. Cancer Res 59, 74–79 (1999). [PubMed] [Google Scholar]
- 84.Sévenet N et al. Constitutional mutations of the hSNF5/INI1 gene predispose to a variety of cancers. Am J Hum Genet 65, 1342–1348, doi: 10.1086/302639 (1999). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 85.Brennan B, Stiller C & Bourdeaut F Extracranial rhabdoid tumours: what we have learned so far and future directions. Lancet Oncol 14, e329–336, doi: 10.1016/s1470-2045(13)70088-3 (2013). [DOI] [PubMed] [Google Scholar]
- 86.Broggi G et al. Atypical teratoid/rhabdoid tumor in adults: a systematic review of the literature with meta-analysis and additional reports of 4 cases. J Neurooncol 157, 1–14, doi: 10.1007/s11060-022-03959-z (2022). [DOI] [PubMed] [Google Scholar]
- 87.Lee RS et al. A remarkably simple genome underlies highly malignant pediatric rhabdoid cancers. J Clin Invest 122, 2983–2988, doi: 10.1172/jci64400 (2012). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 88.Lawrence MS et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 499, 214–218, doi: 10.1038/nature12213 (2013). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 89.Dharia NV et al. A first-generation pediatric cancer dependency map. Nature Genetics 53, 529–538, doi: 10.1038/s41588-021-00819-w (2021). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 90.Betz BL, Strobeck MW, Reisman DN, Knudsen ES & Weissman BE Re-expression of hSNF5/INI1/BAF47 in pediatric tumor cells leads to G1 arrest associated with induction of p16ink4a and activation of RB. Oncogene 21, 5193–5203, doi: 10.1038/sj.onc.1205706 (2002). [DOI] [PubMed] [Google Scholar]
- 91.Schaefer IM & Hornick JL SWI/SNF complex-deficient soft tissue neoplasms: An update. Semin Diagn Pathol 38, 222–231, doi: 10.1053/j.semdp.2020.05.005 (2021). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 92.Smith MJ et al. Frequency of SMARCB1 mutations in familial and sporadic schwannomatosis. Neurogenetics 13, 141–145, doi: 10.1007/s10048-012-0319-8 (2012). [DOI] [PubMed] [Google Scholar]
- 93.Kenworthy CA et al. Bromodomains regulate dynamic targeting of the PBAF chromatin-remodeling complex to chromatin hubs. Biophysical Journal 121, 1738–1752, doi: 10.1016/j.bpj.2022.03.027 (2022). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 94.Varela I et al. Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma. Nature 469, 539–542, doi: 10.1038/nature09639 (2011). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 95.Cancer Genome Atlas Research, N. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature 499, 43–49, doi: 10.1038/nature12222 (2013). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 96.Yao X et al. PBRM1-deficient PBAF complexes target aberrant genomic loci to activate the NF-κB pathway in clear cell renal cell carcinoma. Nature Cell Biology 25, 765–777, doi: 10.1038/s41556-023-01122-y (2023). [DOI] [PubMed] [Google Scholar]
- 97.Sima X et al. The genetic alteration spectrum of the SWI/SNF complex: The oncogenic roles of BRD9 and ACTL6A. PLoS One 14, e0222305, doi: 10.1371/journal.pone.0222305 (2019). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 98.Chang C-Y et al. Increased ACTL6A occupancy within mSWI/SNF chromatin remodelers drives human squamous cell carcinoma. Molecular Cell 81, 4964–4978.e4968, doi: 10.1016/j.molcel.2021.10.005 (2021). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 99.Kadoch C & Crabtree GR Reversible disruption of mSWI/SNF (BAF) complexes by the SS18-SSX oncogenic fusion in synovial sarcoma. Cell 153, 71–85, doi: 10.1016/j.cell.2013.02.036 (2013). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 100.Li J et al. A role for SMARCB1 in synovial sarcomagenesis reveals that SS18-SSX induces canonical BAF destruction. Cancer Discovery, doi: 10.1158/2159-8290.Cd-20-1219 (2021). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 101.Reisman DN, Sciarrotta J, Wang W, Funkhouser WK & Weissman BE Loss of BRG1/BRM in human lung cancer cell lines and primary lung cancers: correlation with poor prognosis. Cancer Res 63, 560–566 (2003). [PubMed] [Google Scholar]
- 102.Bai J et al. BRG1 is a prognostic marker and potential therapeutic target in human breast cancer. PLoS One 8, e59772, doi: 10.1371/journal.pone.0059772 (2013). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 103.Pyo JS, Son BK, Oh D & Kim EK BRG1 is correlated with poor prognosis in colorectal cancer. Hum Pathol 73, 66–73, doi: 10.1016/j.humpath.2017.12.013 (2018). [DOI] [PubMed] [Google Scholar]
- 104.Le Loarer F et al. SMARCA4 inactivation defines a group of undifferentiated thoracic malignancies transcriptionally related to BAF-deficient sarcomas. Nature Genetics 47, 1200–1205, doi: 10.1038/ng.3399 (2015). [DOI] [PubMed] [Google Scholar]
- 105.Witkowski L et al. Germline and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type. Nat Genet 46, 438–443, doi: 10.1038/ng.2931 (2014). [DOI] [PubMed] [Google Scholar]
- 106.Jelinic P et al. Recurrent SMARCA4 mutations in small cell carcinoma of the ovary. Nat Genet 46, 424–426, doi: 10.1038/ng.2922 (2014). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 107.Ramos P et al. Small cell carcinoma of the ovary, hypercalcemic type, displays frequent inactivating germline and somatic mutations in SMARCA4. Nat Genet 46, 427–429, doi: 10.1038/ng.2928 (2014). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 108.Mullen J, Kato S, Sicklick JK & Kurzrock R Targeting ARID1A mutations in cancer. Cancer Treat Rev 100, 102287, doi: 10.1016/j.ctrv.2021.102287 (2021). [DOI] [PubMed] [Google Scholar]
- 109.Jones S et al. Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma. Science 330, 228–231, doi: 10.1126/science.1196333 (2010). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 110.Wiegand KC et al. ARID1A mutations in endometriosis-associated ovarian carcinomas. N Engl J Med 363, 1532–1543, doi: 10.1056/NEJMoa1008433 (2010). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 111.Wang K et al. Exome sequencing identifies frequent mutation of ARID1A in molecular subtypes of gastric cancer. Nat Genet 43, 1219–1223, doi: 10.1038/ng.982 (2011). [DOI] [PubMed] [Google Scholar]
- 112.Jones S et al. Somatic mutations in the chromatin remodeling gene ARID1A occur in several tumor types. Hum Mutat 33, 100–103, doi: 10.1002/humu.21633 (2012). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 113.Guichard C et al. Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma. Nat Genet 44, 694–698, doi: 10.1038/ng.2256 (2012). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 114.Wu JN & Roberts CW ARID1A mutations in cancer: another epigenetic tumor suppressor? Cancer Discov 3, 35–43, doi: 10.1158/2159-8290.Cd-12-0361 (2013). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 115.D’Ambrosio A et al. Increased genomic instability and reshaping of tissue microenvironment underlie oncogenic properties of Arid1a mutations. Sci Adv 10, eadh4435, doi: 10.1126/sciadv.adh4435 (2024). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 116.Sun X et al. Arid1a Has Context-Dependent Oncogenic and Tumor Suppressor Functions in Liver Cancer. Cancer Cell 32, 574–589.e576, doi: 10.1016/j.ccell.2017.10.007 (2017). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 117.Kelso TWR et al. Chromatin accessibility underlies synthetic lethality of SWI/SNF subunits in ARID1A-mutant cancers. eLife 6, e30506, doi: 10.7554/eLife.30506 (2017). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 118.Li M et al. Inactivating mutations of the chromatin remodeling gene ARID2 in hepatocellular carcinoma. Nat Genet 43, 828–829, doi: 10.1038/ng.903 (2011). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 119.Manceau G et al. Recurrent inactivating mutations of ARID2 in non-small cell lung carcinoma. Int J Cancer 132, 2217–2221, doi: 10.1002/ijc.27900 (2013). [DOI] [PubMed] [Google Scholar]
- 120.Carcamo S et al. Altered BAF occupancy and transcription factor dynamics in PBAF-deficient melanoma. Cell Rep 39, 110637, doi: 10.1016/j.celrep.2022.110637 (2022). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 121.Sokpor G, Xie Y, Rosenbusch J & Tuoc T Chromatin Remodeling BAF (SWI/SNF) Complexes in Neural Development and Disorders. Front Mol Neurosci 10, 243, doi: 10.3389/fnmol.2017.00243 (2017). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 122.Tsurusaki Y et al. Mutations affecting components of the SWI/SNF complex cause Coffin-Siris syndrome. Nat Genet 44, 376–378, doi: 10.1038/ng.2219 (2012). [DOI] [PubMed] [Google Scholar]
- 123.Wieczorek D et al. A comprehensive molecular study on Coffin-Siris and Nicolaides-Baraitser syndromes identifies a broad molecular and clinical spectrum converging on altered chromatin remodeling. Hum Mol Genet 22, 5121–5135, doi: 10.1093/hmg/ddt366 (2013). [DOI] [PubMed] [Google Scholar]
- 124.Santen GW et al. Mutations in SWI/SNF chromatin remodeling complex gene ARID1B cause Coffin-Siris syndrome. Nat Genet 44, 379–380, doi: 10.1038/ng.2217 (2012). [DOI] [PubMed] [Google Scholar]
- 125.Celen C et al. Arid1b haploinsufficient mice reveal neuropsychiatric phenotypes and reversible causes of growth impairment. Elife 6, doi: 10.7554/eLife.25730 (2017). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 126.Cárcamo B, Masotto B, Baquero-Vaquer A, Ceballos-Saenz D & Zapata-Aldana E “Cancer in ARID1A-Coffin-Siris syndrome: Review and report of a child with hepatoblastoma”. Eur J Med Genet 65, 104600, doi: 10.1016/j.ejmg.2022.104600 (2022). [DOI] [PubMed] [Google Scholar]
- 127. Tsherniak A et al. Defining a Cancer Dependency Map. Cell 170, 564–576 e516, doi: 10.1016/j.cell.2017.06.010 (2017). Therapeutic vulnerabilities identified through these unbiased, genome-wide CRISPR perturbation screens have informed strategies to target SWI/SNF-mutant cancers and identified new diseases where targeting SWI/SNF complexes may have anti-tumor potential.
- 128.Dharia NV et al. A first-generation pediatric cancer dependency map. Nat Genet 53, 529–538, doi: 10.1038/s41588-021-00819-w (2021). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 129.Corsello SM et al. Discovering the anti-cancer potential of non-oncology drugs by systematic viability profiling. Nat Cancer 1, 235–248, doi: 10.1038/s43018-019-0018-6 (2020). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 130. Vangamudi B et al. The SMARCA2/4 ATPase Domain Surpasses the Bromodomain as a Drug Target in SWI/SNF-Mutant Cancers: Insights from cDNA Rescue and PFI-3 Inhibitor Studies. Cancer Res 75, 3865–3878, doi: 10.1158/0008-5472.CAN-14-3798 (2015). First identification of bromodomain ligands for SMARCA2/4 that were subsequently repurposed into effective PROTACs.
- 131. Papillon JPN et al. Discovery of Orally Active Inhibitors of Brahma Homolog (BRM)/SMARCA2 ATPase Activity for the Treatment of Brahma Related Gene 1 (BRG1)/SMARCA4-Mutant Cancers. Journal of Medicinal Chemistry 61, 10155–10172, doi: 10.1021/acs.jmedchem.8b01318 (2018). First identification of ATPase inhibitors of SMARCA2/4.
- 132.Richard CC et al. Pharmacologic inhibition of BAF chromatin remodeling complexes as a therapeutic approach to transcription factor-dependent cancers. bioRxiv, 2023.2009.2011.557162, doi: 10.1101/2023.09.11.557162 (2023). [DOI] [Google Scholar]
- 133.Bondeson DP et al. Lessons in PROTAC Design from Selective Degradation with a Promiscuous Warhead. Cell Chem Biol 25, 78–87.e75, doi: 10.1016/j.chembiol.2017.09.010 (2018). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 134.Smith BE et al. Differential PROTAC substrate specificity dictated by orientation of recruited E3 ligase. Nature Communications 10, 131, doi: 10.1038/s41467-018-08027-7 (2019). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 135.Békés M, Langley DR & Crews CM PROTAC targeted protein degraders: the past is prologue. Nature Reviews Drug Discovery 21, 181–200, doi: 10.1038/s41573-021-00371-6 (2022). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 136.Teng M & Gray NS The rise of degrader drugs. Cell Chem Biol 30, 864–878, doi: 10.1016/j.chembiol.2023.06.020 (2023). [DOI] [PubMed] [Google Scholar]
- 137. Farnaby W et al. BAF complex vulnerabilities in cancer demonstrated via structure-based PROTAC design. Nat Chem Biol 15, 672–680, doi: 10.1038/s41589-019-0294-6 (2019). First proof of concept that ATPase subunits of SWI/SNF complexes can be degraded using PROTACs.
- 138.Panditharatna E et al. BAF Complex Maintains Glioma Stem Cells in Pediatric H3K27M Glioma. Cancer Discov 12, 2880–2905, doi: 10.1158/2159-8290.CD-21-1491 (2022). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 139. Kofink C et al. A selective and orally bioavailable VHL-recruiting PROTAC achieves SMARCA2 degradation in vivo. Nat Commun 13, 5969, doi: 10.1038/s41467-022-33430-6 (2022). First SWI/SNF ATPase PROTAC with specificity towards SMARCA2 over SMARCA4.
- 140.Cantley J et al. Selective PROTAC-mediated degradation of SMARCA2 is efficacious in SMARCA4 mutant cancers. Nat Commun 13, 6814, doi: 10.1038/s41467-022-34562-5 (2022). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 141.Yang L et al. Discovery of SMD-3040 as a Potent and Selective SMARCA2 PROTAC Degrader with Strong in vivo Antitumor Activity. Journal of Medicinal Chemistry 66, 10761–10781, doi: 10.1021/acs.jmedchem.3c00953 (2023). [DOI] [PubMed] [Google Scholar]
- 142.Ito K et al. Discovery of PRT3789, a first-in-class potent and selective SMARCA2 degrader inclinical trials for the treatment of patients with SMARCA4 mutated cancers, <https://preludetx.com/wp-content/uploads/2023/10/Ito_SMARCA_preclinical-AACR_NCI-EORTC_poster_Oct2023.pdf> (AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, Boston, MA, October 13, 2023). [Google Scholar]
- 143.Marian CA et al. Small Molecule Targeting of Specific BAF (mSWI/SNF) Complexes for HIV Latency Reversal. Cell Chemical Biology 25, 1443–1455.e1414, doi: 10.1016/j.chembiol.2018.08.004 (2018). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 144.Wang Z et al. Dual ARID1A/ARID1B loss leads to rapid carcinogenesis and disruptive redistribution of BAF complexes. Nature Cancer 1, 909–922, doi: 10.1038/s43018-020-00109-0 (2020). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 145.St Pierre R et al. SMARCE1 deficiency generates a targetable mSWI/SNF dependency in clear cell meningioma. Nat Genet 54, 861–873, doi: 10.1038/s41588-022-01077-0 (2022). [DOI] [PubMed] [Google Scholar]
- 146.McBride MJ et al. The SS18-SSX Fusion Oncoprotein Hijacks BAF Complex Targeting and Function to Drive Synovial Sarcoma. Cancer Cell 33, 1128–1141 e1127, doi: 10.1016/j.ccell.2018.05.002 (2018). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 147.Clark PG et al. LP99: Discovery and Synthesis of the First Selective BRD7/9 Bromodomain Inhibitor. Angew Chem Int Ed Engl 54, 6217–6221, doi: 10.1002/anie.201501394 (2015). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 148.Hohmann AF et al. Sensitivity and engineered resistance of myeloid leukemia cells to BRD9 inhibition. Nat Chem Biol 12, 672–679, doi: 10.1038/nchembio.2115 (2016). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 149.Krämer KF, Moreno N, Frühwald MC & Kerl K BRD9 Inhibition, Alone or in Combination with Cytostatic Compounds as a Therapeutic Approach in Rhabdoid Tumors. International Journal of Molecular Sciences 18 (2017). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 150. Theodoulou NH et al. Discovery of I-BRD9, a Selective Cell Active Chemical Probe for Bromodomain Containing Protein 9 Inhibition. J Med Chem 59, 1425–1439, doi: 10.1021/acs.jmedchem.5b00256 (2016). Initial development of bromodomain inhibitors that specifically targeting BRD9.
- 151. Remillard D et al. Degradation of the BAF Complex Factor BRD9 by Heterobifunctional Ligands. Angewandte Chemie International Edition 56, 5738–5743, doi: 10.1002/anie.201611281 (2017). First report of degraders of BRD9.
- 152.Weisberg E et al. BRD9 degraders as chemosensitizers in acute leukemia and multiple myeloma. Blood Cancer J 12, 110, doi: 10.1038/s41408-022-00704-7 (2022). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 153.Ordonez-Rubiano SC et al. Rational Design and Development of Selective BRD7 Bromodomain Inhibitors and Their Activity in Prostate Cancer. J Med Chem 66, 11250–11270, doi: 10.1021/acs.jmedchem.3c00671 (2023). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 154.Shishodia S et al. Selective and Cell-Active PBRM1 Bromodomain Inhibitors Discovered through NMR Fragment Screening. J Med Chem 65, 13714–13735, doi: 10.1021/acs.jmedchem.2c00864 (2022). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 155.Cochran AG & Flynn M GNE-235: A Lead Compound Selective for the Second Bromodomain of PBRM1. Journal of Medicinal Chemistry 66, 13116–13134, doi: 10.1021/acs.jmedchem.3c01149 (2023). [DOI] [PubMed] [Google Scholar]
- 156.Knutson SK et al. Durable tumor regression in genetically altered malignant rhabdoid tumors by inhibition of methyltransferase EZH2. Proc Natl Acad Sci U S A 110, 7922–7927, doi: 10.1073/pnas.1303800110 (2013). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 157.Muscat A et al. Low-Dose Histone Deacetylase Inhibitor Treatment Leads to Tumor Growth Arrest and Multi-Lineage Differentiation of Malignant Rhabdoid Tumors. Clin Cancer Res 22, 3560–3570, doi: 10.1158/1078-0432.CCR-15-2260 (2016). [DOI] [PubMed] [Google Scholar]
- 158.Kennison JA The Polycomb and trithorax group proteins of Drosophila: trans-regulators of homeotic gene function. Annu Rev Genet 29, 289–303, doi: 10.1146/annurev.ge.29.120195.001445 (1995). [DOI] [PubMed] [Google Scholar]
- 159.Shao Z et al. Stabilization of chromatin structure by PRC1, a Polycomb complex. Cell 98, 37–46, doi: 10.1016/s0092-8674(00)80604-2 (1999). [DOI] [PubMed] [Google Scholar]
- 160.Tamkun JW et al. brahma: a regulator of Drosophila homeotic genes structurally related to the yeast transcriptional activator SNF2/SWI2. Cell 68, 561–572, doi: 10.1016/0092-8674(92)90191-e (1992). [DOI] [PubMed] [Google Scholar]
- 161.Kim KH & Roberts CWM Targeting EZH2 in cancer. Nature Medicine 22, 128–134, doi: 10.1038/nm.4036 (2016). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 162.Kadoch C et al. Dynamics of BAF-Polycomb complex opposition on heterochromatin in normal and oncogenic states. Nat Genet 49, 213–222, doi: 10.1038/ng.3734 (2017). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 163.McCabe MT et al. EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature 492, 108–112, doi: 10.1038/nature11606 (2012). [DOI] [PubMed] [Google Scholar]
- 164.Campbell JE et al. EPZ011989, A Potent, Orally-Available EZH2 Inhibitor with Robust in Vivo Activity. ACS Medicinal Chemistry Letters 6, 491–495, doi: 10.1021/acsmedchemlett.5b00037 (2015). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 165.Knutson SK et al. A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells. Nat Chem Biol 8, 890–896, doi: 10.1038/nchembio.1084 (2012). [DOI] [PubMed] [Google Scholar]
- 166.Qi W et al. Selective inhibition of Ezh2 by a small molecule inhibitor blocks tumor cells proliferation. Proc Natl Acad Sci U S A 109, 21360–21365, doi: 10.1073/pnas.1210371110 (2012). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 167.Italiano A et al. Tazemetostat, an EZH2 inhibitor, in relapsed or refractory B-cell non-Hodgkin lymphoma and advanced solid tumours: a first-in-human, open-label, phase 1 study. The Lancet Oncology 19, 649–659, doi: 10.1016/S1470-2045(18)30145-1 (2018). [DOI] [PubMed] [Google Scholar]
- 168.Gounder M et al. Tazemetostat in advanced epithelioid sarcoma with loss of INI1/SMARCB1: an international, open-label, phase 2 basket study. Lancet Oncol 21, 1423–1432, doi: 10.1016/S1470-2045(20)30451-4 (2020). [DOI] [PubMed] [Google Scholar]
- 169.Chi SN et al. Phase I study of tazemetostat, an enhancer of zeste homolog-2 inhibitor, in pediatric pts with relapsed/refractory integrase interactor 1-negative tumors. Journal of Clinical Oncology 38, 10525–10525, doi: 10.1200/JCO.2020.38.15_suppl.10525 (2020). [DOI] [Google Scholar]
- 170.Chi SN et al. Tazemetostat for tumors harboring SMARCB1/SMARCA4 or EZH2 alterations: results from NCI-COG pediatric MATCH APEC1621C. J Natl Cancer Inst 115, 1355–1363, doi: 10.1093/jnci/djad085 (2023). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 171.Rosen EY, Shukla NN & Glade Bender JL EZH2 inhibition: it’s all about the context. JNCI: Journal of the National Cancer Institute 115, 1246–1248, doi: 10.1093/jnci/djad141 (2023). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 172.Drosos Y et al. NSD1 mediates antagonism between SWI/SNF and polycomb complexes and is required for transcriptional activation upon EZH2 inhibition. Mol Cell 82, 2472–2489.e2478, doi: 10.1016/j.molcel.2022.04.015 (2022). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 173.Kazansky Y et al. Overcoming clinical resistance to EZH2 inhibition using rational epigenetic combination therapy. Cancer Discovery, doi: 10.1158/2159-8290.CD-23-0110 (2024). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 174.Torchia J et al. Integrated (epi)-Genomic Analyses Identify Subgroup-Specific Therapeutic Targets in CNS Rhabdoid Tumors. Cancer Cell 30, 891–908, doi: 10.1016/j.ccell.2016.11.003 (2016). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 175.Shinohara H et al. Dual targeting of EZH1 and EZH2 for the treatment of malignant rhabdoid tumors. Mol Ther Oncolytics 27, 14–25, doi: 10.1016/j.omto.2022.09.006 (2022). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 176.Xu B et al. Selective inhibition of EZH2 and EZH1 enzymatic activity by a small molecule suppresses MLL-rearranged leukemia. Blood 125, 346–357, doi: 10.1182/blood-2014-06-581082 (2015). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 177.Honma D et al. Novel orally bioavailable EZH1/2 dual inhibitors with greater antitumor efficacy than an EZH2 selective inhibitor. Cancer Sci 108, 2069–2078, doi: 10.1111/cas.13326 (2017). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 178.Xu K et al. EZH2 oncogenic activity in castration-resistant prostate cancer cells is Polycomb-independent. Science 338, 1465–1469, doi: 10.1126/science.1227604 (2012). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 179.Zhao Y et al. EZH2 cooperates with gain-of-function p53 mutants to promote cancer growth and metastasis. Embo j 38, doi: 10.15252/embj.201899599 (2019). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 180.Kim J et al. Polycomb- and Methylation-Independent Roles of EZH2 as a Transcription Activator. Cell Rep 25, 2808–2820.e2804, doi: 10.1016/j.celrep.2018.11.035 (2018). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 181.Ma A et al. Discovery of a first-in-class EZH2 selective degrader. Nat Chem Biol 16, 214–222, doi: 10.1038/s41589-019-0421-4 (2020). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 182.Hsu JH-R et al. EED-Targeted PROTACs Degrade EED, EZH2, and SUZ12 in the PRC2 Complex. Cell Chemical Biology 27, 41–46.e17, doi: 10.1016/j.chembiol.2019.11.004 (2020). [DOI] [PubMed] [Google Scholar]
- 183.Liu Z et al. Design and Synthesis of EZH2-Based PROTACs to Degrade the PRC2 Complex for Targeting the Noncatalytic Activity of EZH2. Journal of Medicinal Chemistry 64, 2829–2848, doi: 10.1021/acs.jmedchem.0c02234 (2021). [DOI] [PubMed] [Google Scholar]
- 184.Velez J, Kaniskan HÜ & Jin J Recent advances in developing degraders & inhibitors of lysine methyltransferases. Current Opinion in Chemical Biology 76, 102356, doi: 10.1016/j.cbpa.2023.102356 (2023). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 185.Jeong Y et al. Overcoming the therapeutic limitations of EZH2 inhibitors in Burkitt’s lymphoma: a comprehensive study on the combined effects of MS1943 and Ibrutinib. Front Oncol 13, 1252658, doi: 10.3389/fonc.2023.1252658 (2023). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 186.Tu Y et al. Design, Synthesis, and Evaluation of VHL-Based EZH2 Degraders to Enhance Therapeutic Activity against Lymphoma. Journal of Medicinal Chemistry 64, 10167–10184, doi: 10.1021/acs.jmedchem.1c00460 (2021). [DOI] [PubMed] [Google Scholar]
- 187.Zhang C & Li H Molecular targeted therapies for pediatric atypical teratoid/rhabdoid tumors. Pediatr Investig 6, 111–122, doi: 10.1002/ped4.12325 (2022). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 188.Wanior M, Kramer A, Knapp S & Joerger AC Exploiting vulnerabilities of SWI/SNF chromatin remodelling complexes for cancer therapy. Oncogene 40, 3637–3654, doi: 10.1038/s41388-021-01781-x (2021). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 189.Centore RC, Sandoval GJ, Soares LMM, Kadoch C & Chan HM Mammalian SWI/SNF Chromatin Remodeling Complexes: Emerging Mechanisms and Therapeutic Strategies. Trends in Genetics 36, 936–950, doi: 10.1016/j.tig.2020.07.011 (2020). [DOI] [PubMed] [Google Scholar]
- 190.Xue Y et al. CDK4/6 inhibitors target SMARCA4-determined cyclin D1 deficiency in hypercalcemic small cell carcinoma of the ovary. Nature Communications 10, 558, doi: 10.1038/s41467-018-06958-9 (2019). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 191.Xue Y et al. SMARCA4 loss is synthetic lethal with CDK4/6 inhibition in non-small cell lung cancer. Nature Communications 10, 557, doi: 10.1038/s41467-019-08380-1 (2019). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 192.Schubert NA et al. Target actionability review to evaluate CDK4/6 as a therapeutic target in paediatric solid and brain tumours. European Journal of Cancer 170, 196–208, doi: 10.1016/j.ejca.2022.04.028 (2022). [DOI] [PubMed] [Google Scholar]
- 193.Geoerger B et al. A Phase I Study of the CDK4/6 Inhibitor Ribociclib (LEE011) in Pediatric Patients with Malignant Rhabdoid Tumors, Neuroblastoma, and Other Solid Tumors. Clinical Cancer Research 23, 2433–2441, doi: 10.1158/1078-0432.CCR-16-2898 (2017). [DOI] [PubMed] [Google Scholar]
- 194.Wu C et al. Targeting AURKA-CDC25C axis to induce synthetic lethality in ARID1A-deficient colorectal cancer cells. Nat Commun 9, 3212, doi: 10.1038/s41467-018-05694-4 (2018). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 195.Lee S, Cimica V, Ramachandra N, Zagzag D & Kalpana GV Aurora A is a repressed effector target of the chromatin remodeling protein INI1/hSNF5 required for rhabdoid tumor cell survival. Cancer Res 71, 3225–3235, doi: 10.1158/0008-5472.CAN-10-2167 (2011). [DOI] [PubMed] [Google Scholar]
- 196.Tagal V et al. SMARCA4-inactivating mutations increase sensitivity to Aurora kinase A inhibitor VX-680 in non-small cell lung cancers. Nat Commun 8, 14098, doi: 10.1038/ncomms14098 (2017). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 197.Mou PK et al. Aurora kinase A, a synthetic lethal target for precision cancer medicine. Experimental & Molecular Medicine 53, 835–847, doi: 10.1038/s12276-021-00635-6 (2021). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 198.Rodriguez Freixinos V et al. Antitumor activity, safety and predictive biomarker results of ENMD-2076 administered to patients (pts) with recurrent ovarian clear cell carcinoma (OCCC): A trial of the Princess Margaret Phase II Consortium. Journal of Clinical Oncology 34, 5564–5564, doi: 10.1200/JCO.2016.34.15_suppl.5564 (2016). [DOI] [Google Scholar]
- 199.Upadhyaya S et al. Phase II study of alisertib as a single agent in recurrent or progressive atypical teratoid rhabdoid tumors. Journal of Clinical Oncology 38, 10542–10542, doi: 10.1200/JCO.2020.38.15_suppl.10542 (2020). [DOI] [Google Scholar]
- 200.Adhikari B et al. PROTAC-mediated degradation reveals a non-catalytic function of AURORA-A kinase. Nat Chem Biol 16, 1179–1188, doi: 10.1038/s41589-020-00652-y (2020). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 201.Oberlick EM et al. Small-Molecule and CRISPR Screening Converge to Reveal Receptor Tyrosine Kinase Dependencies in Pediatric Rhabdoid Tumors. Cell Rep 28, 2331–2344 e2338, doi: 10.1016/j.celrep.2019.07.021 (2019). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 202.Miller RE et al. Synthetic Lethal Targeting of ARID1A-Mutant Ovarian Clear Cell Tumors with Dasatinib. Mol Cancer Ther 15, 1472–1484, doi: 10.1158/1535-7163.Mct-15-0554 (2016). [DOI] [PubMed] [Google Scholar]
- 203.Lang JD et al. Ponatinib Shows Potent Antitumor Activity in Small Cell Carcinoma of the Ovary Hypercalcemic Type (SCCOHT) through Multikinase Inhibition. Clinical Cancer Research 24, 1932–1943, doi: 10.1158/1078-0432.CCR-17-1928 (2018). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 204.de Miguel FJ et al. Mammalian SWI/SNF chromatin remodeling complexes promote tyrosine kinase inhibitor resistance in EGFR-mutant lung cancer. Cancer Cell 41, 1516–1534 e1519, doi: 10.1016/j.ccell.2023.07.005 (2023). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 205.Sadek M, Sheth A, Zimmerman G, Hays E & Vélez-Cruz R The role of SWI/SNF chromatin remodelers in the repair of DNA double strand breaks and cancer therapy. Front Cell Dev Biol 10, 1071786, doi: 10.3389/fcell.2022.1071786 (2022). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 206.Shen J et al. ARID1A Deficiency Impairs the DNA Damage Checkpoint and Sensitizes Cells to PARP Inhibitors. Cancer Discovery 5, 752–767, doi: 10.1158/2159-8290.CD-14-0849 (2015). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 207.Chen Y et al. A PARP1-BRG1-SIRT1 axis promotes HR repair by reducing nucleosome density at DNA damage sites. Nucleic Acids Res 47, 8563–8580, doi: 10.1093/nar/gkz592 (2019). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 208.Kakarougkas A et al. Requirement for PBAF in transcriptional repression and repair at DNA breaks in actively transcribed regions of chromatin. Mol Cell 55, 723–732, doi: 10.1016/j.molcel.2014.06.028 (2014). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 209.Park Y et al. Loss of ARID1A in Tumor Cells Renders Selective Vulnerability to Combined Ionizing Radiation and PARP Inhibitor Therapy. Clin Cancer Res 25, 5584–5594, doi: 10.1158/1078-0432.Ccr-18-4222 (2019). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 210.Williamson CT et al. ATR inhibitors as a synthetic lethal therapy for tumours deficient in ARID1A. Nat Commun 7, 13837, doi: 10.1038/ncomms13837 (2016). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 211.Curtin NJ & Szabo C Poly(ADP-ribose) polymerase inhibition: past, present and future. Nature Reviews Drug Discovery 19, 711–736, doi: 10.1038/s41573-020-0076-6 (2020). [DOI] [PubMed] [Google Scholar]
- 212.Szczepanski A et al. A SWI/SNF-dependent transcriptional regulation mediated by POU2AF2/C11orf53 at enhancer. Nature Communications 15, 2067, doi: 10.1038/s41467-024-46492-5 (2024). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 213.He T et al. Targeting the mSWI/SNF Complex in POU2F-POU2AF Transcription Factor-Driven Malignancies. bioRxiv, doi: 10.1101/2024.01.22.576669 (2024). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 214.Rago F et al. The Discovery of SWI/SNF Chromatin Remodeling Activity as a Novel and Targetable Dependency in Uveal Melanoma. Molecular Cancer Therapeutics 19, 2186–2195, doi: 10.1158/1535-7163.MCT-19-1013 (2020). [DOI] [PubMed] [Google Scholar]
- 215.Rago F et al. Exquisite Sensitivity to Dual BRG1/BRM ATPase Inhibitors Reveals Broad SWI/SNF Dependencies in Acute Myeloid Leukemia. Mol Cancer Res 20, 361–372, doi: 10.1158/1541-7786.Mcr-21-0390 (2022). [DOI] [PubMed] [Google Scholar]
- 216.Mo Y et al. Epigenome Programming by H3.3K27M Mutation Creates a Dependence of Pediatric Glioma on SMARCA4. Cancer Discov 12, 2906–2929, doi: 10.1158/2159-8290.Cd-21-1492 (2022). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 217.Panditharatna E et al. BAF Complex Maintains Glioma Stem Cells in Pediatric H3K27M Glioma. Cancer Discovery 12, 2880–2905, doi: 10.1158/2159-8290.CD-21-1491 (2022). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 218.Bradner JE, Hnisz D & Young RA Transcriptional Addiction in Cancer. Cell 168, 629–643, doi: 10.1016/j.cell.2016.12.013 (2017). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 219.Henley MJ & Koehler AN Advances in targeting ‘undruggable’ transcription factors with small molecules. Nature Reviews Drug Discovery 20, 669–688, doi: 10.1038/s41573-021-00199-0 (2021). [DOI] [PubMed] [Google Scholar]
- 220.Chambers C et al. SWI/SNF Blockade Disrupts PU.1-Directed Enhancer Programs in Normal Hematopoietic Cells and Acute Myeloid Leukemia. Cancer Res 83, 983–996, doi: 10.1158/0008-5472.CAN-22-2129 (2023). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 221.Warren F et al. BRG1/BRM inhibitor targets AML stem cells and exerts superior preclinical efficacy combined with BET or Menin inhibitor. bioRxiv, 2023.2009.2028.560054, doi: 10.1101/2023.09.28.560054 (2023). [DOI] [Google Scholar]
- 222.Barisic D, Stadler MB, Iurlaro M & Schübeler D Mammalian ISWI and SWI/SNF selectively mediate binding of distinct transcription factors. Nature 569, 136–140, doi: 10.1038/s41586-019-1115-5 (2019). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 223. Martin BJE et al. Global identification of SWI/SNF targets reveals compensation by EP400. Cell 186, 5290–5307.e5226, doi: 10.1016/j.cell.2023.10.006 (2023). Defines a compensatory mechanism of chromatin regulation upon inhibition of SWI/SNF complexes.
- 224.Taherbhoy A Targeting Transcription Factor – BAF Interactions in Cancer, <https://foghorntx.com/wp-content/uploads/2023/04/Taherbhoy_DDC_2023_slides.pdf> (Drug Discovery Chemistry, San Diego, CA, April 13, 2023). [Google Scholar]
- 225.Sharma SV et al. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell 141, 69–80, doi: 10.1016/j.cell.2010.02.027 (2010). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 226.Leonetti A et al. Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer. British Journal of Cancer 121, 725–737, doi: 10.1038/s41416-019-0573-8 (2019). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 227.Vinogradova M et al. An inhibitor of KDM5 demethylases reduces survival of drug-tolerant cancer cells. Nat Chem Biol 12, 531–538, doi: 10.1038/nchembio.2085 (2016). [DOI] [PubMed] [Google Scholar]
- 228.Wang N, Ma T & Yu B Targeting epigenetic regulators to overcome drug resistance in cancers. Signal Transduction and Targeted Therapy 8, 69, doi: 10.1038/s41392-023-01341-7 (2023). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 229.Zebley CC & Youngblood B Mechanisms of T cell exhaustion guiding next-generation immunotherapy. Trends in Cancer 8, 726–734, doi: 10.1016/j.trecan.2022.04.004 (2022). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 230.Sen DR et al. The epigenetic landscape of T cell exhaustion. Science 354, 1165–1169, doi:doi: 10.1126/science.aae0491 (2016). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 231.Philip M et al. Chromatin states define tumour-specific T cell dysfunction and reprogramming. Nature 545, 452–456, doi: 10.1038/nature22367 (2017). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 232.Gennert DG et al. Dynamic chromatin regulatory landscape of human CAR T cell exhaustion. Proc Natl Acad Sci U S A 118, doi: 10.1073/pnas.2104758118 (2021). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 233.Prinzing B et al. Deleting DNMT3A in CAR T cells prevents exhaustion and enhances antitumor activity. Science Translational Medicine 13, eabh0272, doi:doi: 10.1126/scitranslmed.abh0272 (2021). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 234.Fraietta JA et al. Disruption of TET2 promotes the therapeutic efficacy of CD19-targeted T cells. Nature 558, 307–312, doi: 10.1038/s41586-018-0178-z (2018). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 235.Jain N et al. TET2 guards against unchecked BATF3-induced CAR T cell expansion. Nature 615, 315–322, doi: 10.1038/s41586-022-05692-z (2023). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 236. Guo A et al. cBAF complex components and MYC cooperate early in CD8(+) T cell fate. Nature 607, 135–141, doi: 10.1038/s41586-022-04849-0 (2022). Identification of SWI/SNF as a critical regulator of T-cell fate that rationalizes exploring the use of SWI/SNF inhibitors to enhance response to immunotherapy.
- 237.Battistello E et al. Stepwise activities of mSWI/SNF family chromatin remodeling complexes direct T cell activation and exhaustion. Mol Cell 83, 1216–1236 e1212, doi: 10.1016/j.molcel.2023.02.026 (2023). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 238.Baxter AE et al. The SWI/SNF chromatin remodeling complexes BAF and PBAF differentially regulate epigenetic transitions in exhausted CD8(+) T cells. Immunity 56, 1320–1340 e1310, doi: 10.1016/j.immuni.2023.05.008 (2023). [DOI] [PubMed] [Google Scholar]
- 239.Belk JA et al. Genome-wide CRISPR screens of T cell exhaustion identify chromatin remodeling factors that limit T cell persistence. Cancer Cell 40, 768–786 e767, doi: 10.1016/j.ccell.2022.06.001 (2022). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 240.Rebendenne A et al. Bidirectional genome-wide CRISPR screens reveal host factors regulating SARS-CoV-2, MERS-CoV and seasonal HCoVs. Nature Genetics 54, 1090–1102, doi: 10.1038/s41588-022-01110-2 (2022). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 241. Wei J et al. Pharmacological disruption of mSWI/SNF complex activity restricts SARS-CoV-2 infection. Nature Genetics 55, 471–483, doi: 10.1038/s41588-023-01307-z (2023). Demonstrates that SWI/SNF complexes are essential host factors during SARS-CoV-2 infection, raising the question of whether SWI/SNF inhibitors could be useful in treating infectious diseases.
- 242.Hong KB & An H Degrader–Antibody Conjugates: Emerging New Modality. Journal of Medicinal Chemistry 66, 140–148, doi: 10.1021/acs.jmedchem.2c01791 (2023). [DOI] [PubMed] [Google Scholar]
- 243.Shen F et al. A Cell-Permeant Nanobody-Based Degrader That Induces Fetal Hemoglobin. ACS Cent Sci 8, 1695–1703, doi: 10.1021/acscentsci.2c00998 (2022). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 244.Yin M et al. Evolution of nanobodies specific for BCL11A. Proc Natl Acad Sci U S A 120, e2218959120, doi: 10.1073/pnas.2218959120 (2023). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 245.Gourisankar S et al. Rewiring cancer drivers to activate apoptosis. Nature 620, 417–425, doi: 10.1038/s41586-023-06348-2 (2023). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 246.Lionel C, David M, Brenna S, David LL & Asad MT Hijacking the transcriptional activation potential of the BAF complex via Induced Proximity. bioRxiv, 2023.2012.2018.572217, doi: 10.1101/2023.12.18.572217 (2023). [DOI] [Google Scholar]
- 247.Sen P et al. The SnAC domain of SWI/SNF is a histone anchor required for remodeling. Mol Cell Biol 33, 360–370, doi: 10.1128/mcb.00922-12 (2013). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 248.Valencia AM et al. Recurrent SMARCB1 Mutations Reveal a Nucleosome Acidic Patch Interaction Site That Potentiates mSWI/SNF Complex Chromatin Remodeling. Cell 179, 1342–1356 e1323, doi: 10.1016/j.cell.2019.10.044 (2019). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 249.Allen MD, Freund SM, Zinzalla G & Bycroft M The SWI/SNF Subunit INI1 Contains an N-Terminal Winged Helix DNA Binding Domain that Is a Target for Mutations in Schwannomatosis. Structure 23, 1344–1349, doi: 10.1016/j.str.2015.04.021 (2015). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 250.Howard TP AT, Song MR, Giacomelli AO, Wang X, Hong AL, Dharia NV, Wang S, Vazquez F,, Pham MT, M. A., Wachter F, Bird GH, Kugener G, Oberlick EM, Rees MG, Tiv HL, Hwang JH, Walsh KH, C. A., Krill-Burger JM, Tsherniak A, Gokhale PC, Park PJ, Stegmaier K, Walensky LD, Hahn WC, & CWM. R. MDM2 and MDM4 Are Therapeutic Vulnerabilities in Malignant Rhabdoid Tumors. Cancer Res 79, 2404–2414, doi: 10.17504/protocols.io.wh4fb8w (2019). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 251.Hong AL et al. Renal medullary carcinomas depend upon SMARCB1 loss and are sensitive to proteasome inhibition. eLife 8, e44161, doi: 10.7554/eLife.44161 (2019). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 252.Howard TP et al. Rhabdoid Tumors Are Sensitive to the Protein-Translation Inhibitor Homoharringtonine. Clin Cancer Res 26, 4995–5006, doi: 10.1158/1078-0432.CCR-19-2717 (2020). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 253.Soldi R et al. The novel reversible LSD1 inhibitor SP-2577 promotes anti-tumor immunity in SWItch/Sucrose-NonFermentable (SWI/SNF) complex mutated ovarian cancer. PLoS One 15, e0235705, doi: 10.1371/journal.pone.0235705 (2020). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 254.Lissanu Deribe Y et al. Mutations in the SWI/SNF complex induce a targetable dependence on oxidative phosphorylation in lung cancer. Nat Med 24, 1047–1057, doi: 10.1038/s41591-018-0019-5 (2018). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 255.Shorstova T et al. SWI/SNF-Compromised Cancers Are Susceptible to Bromodomain Inhibitors. Cancer Research 79, 2761–2774, doi: 10.1158/0008-5472.CAN-18-1545 (2019). [DOI] [PubMed] [Google Scholar]
- 256.Ehrenhöfer-Wölfer K et al. SMARCA2-deficiency confers sensitivity to targeted inhibition of SMARCA4 in esophageal squamous cell carcinoma cell lines. Scientific Reports 9, 11661, doi: 10.1038/s41598-019-48152-x (2019). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 257.Rehman H et al. ARID1A-deficient bladder cancer is dependent on PI3K signaling and sensitive to EZH2 and PI3K inhibitors. JCI Insight 7, doi: 10.1172/jci.insight.155899 (2022). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 258.Park Y et al. Loss of ARID1A in Tumor Cells Renders Selective Vulnerability to Combined Ionizing Radiation and PARP Inhibitor Therapy. Clinical Cancer Research 25, 5584–5594, doi: 10.1158/1078-0432.CCR-18-4222 (2019). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 259.Bitler BG et al. ARID1A-mutated ovarian cancers depend on HDAC6 activity. Nat Cell Biol 19, 962–973, doi: 10.1038/ncb3582 (2017). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 260.Ogiwara H et al. Targeting the Vulnerability of Glutathione Metabolism in ARID1A-Deficient Cancers. Cancer Cell 35, 177–190.e178, doi: 10.1016/j.ccell.2018.12.009 (2019). [DOI] [PubMed] [Google Scholar]
- 261.Jones SE et al. ATR Is a Therapeutic Target in Synovial Sarcoma. Cancer Research 77, 7014–7026, doi: 10.1158/0008-5472.CAN-17-2056 (2017). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 262.Banito A et al. The SS18-SSX Oncoprotein Hijacks KDM2B-PRC1.1 to Drive Synovial Sarcoma. Cancer Cell 33, 527–541.e528, doi: 10.1016/j.ccell.2018.01.018 (2018). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 263.Li Y et al. The emerging role of ISWI chromatin remodeling complexes in cancer. Journal of Experimental & Clinical Cancer Research 40, 346, doi: 10.1186/s13046-021-02151-x (2021). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 264.Whitehouse I, Rando OJ, Delrow J & Tsukiyama T Chromatin remodelling at promoters suppresses antisense transcription. Nature 450, 1031–1035, doi: 10.1038/nature06391 (2007). [DOI] [PubMed] [Google Scholar]
- 265.Kishtagari A et al. A First-in-Class Inhibitor of ISWI-Mediated (ATP-Dependent) Transcription Repression Releases Terminal-Differentiation in AML Cells While Sparing Normal Hematopoiesis. Blood 132, 216, doi: 10.1182/blood-2018-99-119311 (2018). [DOI] [Google Scholar]
- 266.Park SG, Lee D, Seo HR, Lee SA & Kwon J Cytotoxic activity of bromodomain inhibitor NVS-CECR2–1 on human cancer cells. Sci Rep 10, 16330, doi: 10.1038/s41598-020-73500-7 (2020). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 267.Bevill SM et al. GSK2801, a BAZ2/BRD9 Bromodomain Inhibitor, Synergizes with BET Inhibitors to Induce Apoptosis in Triple-Negative Breast Cancer. Mol Cancer Res 17, 1503–1518, doi: 10.1158/1541-7786.Mcr-18-1121 (2019). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 268.Kirberger SE et al. Selectivity, ligand deconstruction, and cellular activity analysis of a BPTF bromodomain inhibitor. Org Biomol Chem 17, 2020–2027, doi: 10.1039/c8ob02599a (2019). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 269.Zahid H et al. New Design Rules for Developing Potent Cell-Active Inhibitors of the Nucleosome Remodeling Factor (NURF) via BPTF Bromodomain Inhibition. Journal of Medicinal Chemistry 64, 13902–13917, doi: 10.1021/acs.jmedchem.1c01294 (2021). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 270.Manning BJ & Yusufzai T The ATP-dependent chromatin remodeling enzymes CHD6, CHD7, and CHD8 exhibit distinct nucleosome binding and remodeling activities. J Biol Chem 292, 11927–11936, doi: 10.1074/jbc.M117.779470 (2017). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 271.Quan J & Yusufzai T The tumor suppressor chromodomain helicase DNA-binding protein 5 (CHD5) remodels nucleosomes by unwrapping. J Biol Chem 289, 20717–20726, doi: 10.1074/jbc.M114.568568 (2014). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 272.Bagchi A et al. CHD5 is a tumor suppressor at human 1p36. Cell 128, 459–475, doi: 10.1016/j.cell.2006.11.052 (2007). [DOI] [PubMed] [Google Scholar]
- 273.Burkhardt L et al. CHD1 is a 5q21 tumor suppressor required for ERG rearrangement in prostate cancer. Cancer Res 73, 2795–2805, doi: 10.1158/0008-5472.Can-12-1342 (2013). [DOI] [PubMed] [Google Scholar]
- 274.Zhao D et al. Synthetic essentiality of chromatin remodelling factor CHD1 in PTEN-deficient cancer. Nature 542, 484–488, doi: 10.1038/nature21357 (2017). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 275.Heshmati Y et al. Identification of CHD4 As a Potential Therapeutic Target of Acute Myeloid Leukemia. Blood 128, 1648, doi: 10.1182/blood.V128.22.1648.1648 (2016). [DOI] [Google Scholar]
- 276.Sperlazza J et al. Depletion of the chromatin remodeler CHD4 sensitizes AML blasts to genotoxic agents and reduces tumor formation. Blood 126, 1462–1472, doi: 10.1182/blood-2015-03-631606 (2015). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 277.Xia L et al. CHD4 Has Oncogenic Functions in Initiating and Maintaining Epigenetic Suppression of Multiple Tumor Suppressor Genes. Cancer Cell 31, 653–668.e657, doi: 10.1016/j.ccell.2017.04.005 (2017). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 278.Cheng W, Su Y & Xu F CHD1L: a novel oncogene. Mol Cancer 12, 170, doi: 10.1186/1476-4598-12-170 (2013). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 279.Abbott JM et al. First-in-Class Inhibitors of Oncogenic CHD1L with Preclinical Activity against Colorectal Cancer. Mol Cancer Ther 19, 1598–1612, doi: 10.1158/1535-7163.Mct-20-0106 (2020). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 280.Prigaro BJ et al. Design, Synthesis, and Biological Evaluation of the First Inhibitors of Oncogenic CHD1L. J Med Chem 65, 3943–3961, doi: 10.1021/acs.jmedchem.1c01778 (2022). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 281.Farnung L, Vos SM, Wigge C & Cramer P Nucleosome–Chd1 structure and implications for chromatin remodelling. Nature 550, 539–542, doi: 10.1038/nature24046 (2017). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 282.Eustermann S et al. Structural basis for ATP-dependent chromatin remodelling by the INO80 complex. Nature 556, 386–390, doi: 10.1038/s41586-018-0029-y (2018). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 283.Ayala R et al. Structure and regulation of the human INO80-nucleosome complex. Nature 556, 391–395, doi: 10.1038/s41586-018-0021-6 (2018). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 284.Pradhan SK et al. EP400 Deposits H3.3 into Promoters and Enhancers during Gene Activation. Molecular Cell 61, 27–38, doi: 10.1016/j.molcel.2015.10.039 (2016). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 285.Mizuguchi G et al. ATP-Driven Exchange of Histone H2AZ Variant Catalyzed by SWR1 Chromatin Remodeling Complex. Science 303, 343–348, doi: 10.1126/science.1090701 (2004). [DOI] [PubMed] [Google Scholar]
- 286.Zhang S et al. INO80 is required for oncogenic transcription and tumor growth in non-small cell lung cancer. Oncogene 36, 1430–1439, doi: 10.1038/onc.2016.311 (2017). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 287.Zhou B et al. INO80 governs superenhancer-mediated oncogenic transcription and tumor growth in melanoma. Genes Dev 30, 1440–1453, doi: 10.1101/gad.277178.115 (2016). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 288.Prendergast L et al. Resolution of R-loops by INO80 promotes DNA replication and maintains cancer cell proliferation and viability. Nat Commun 11, 4534, doi: 10.1038/s41467-020-18306-x (2020). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 289.Lee SA et al. INO80 haploinsufficiency inhibits colon cancer tumorigenesis via replication stress-induced apoptosis. Oncotarget 8, 115041–115053, doi: 10.18632/oncotarget.22984 (2017). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 290.Remillard D et al. Chemoproteomics Enabled Discovery of Selective Probes for NuA4 Factor BRD8. ACS Chem Biol 16, 2185–2192, doi: 10.1021/acschembio.1c00256 (2021). [DOI] [PubMed] [Google Scholar]
- 291.Londregan AT et al. Discovery of High-Affinity Small-Molecule Binders of the Epigenetic Reader YEATS4. J Med Chem 66, 460–472, doi: 10.1021/acs.jmedchem.2c01421 (2023). [DOI] [PubMed] [Google Scholar]
- 292.Coffey K et al. Characterisation of a Tip60 specific inhibitor, NU9056, in prostate cancer. PLoS One 7, e45539, doi: 10.1371/journal.pone.0045539 (2012). [DOI] [PMC free article] [PubMed] [Google Scholar]