MYC as a Target for Cancer Treatment: from Undruggable to Druggable?

Abstract

MYC is one of the most frequently altered genes in cancer with an estimated 70% prevalence of deregulation. Deregulated MYC is believed to promote cancer formation/progression via multiple mechanisms including tumour cell intrinsic mechanisms, altering the tumour microenvironment and promoting host immune suppression. Owing to the high prevalence of alterations and its causative role in tumorigenesis, MYC is a highly attractive target for new anticancer therapies. However, as MYC lacks a readily identifiably pocket for potential low molecular weight inhibitors and is predominantly located in the cell nucleus, it has proved difficult to target using standard pharmacological approaches. Recently, however, these problems appear to have been successfully resolved, with the discovery of promising anti-MYC compounds such as Omomyc or MYCi975. Both Omomyc and MYCi975 exhibit anti-cancer activity in several different animal models, with apparently little short-term toxicity. Furthermore, consistent with the ability of MYC to promote a pro-tumour microenvironment and induce immune evasion, treatment with Omomyc or MYCi975 was shown to increase uptake of anti-tumour lymphocytes and enhance response to immunotherapy. Currently, at least five anti-MYC compounds are being evaluated for potential anti-cancer activity in clinical trials. Results from a phase I trial with OMO-103 (a form of Omomyc) suggest that the inhibitor is well tolerated, with most of its adverse effects being at grade 1 level. Evidence of target inhibition was the finding of decreased expression of multiple MYC regulated genes.

Key Points

MYC is one of the most frequently altered genes in cancer and thus a potential new anti-cancer target.

Historically, MYC has been difficult to target using pharmacological strategies, owing to the absence of a readily identifiable hydrophobic pocket for the binding of potential low molecular weight drugs.

These historical problems appear to have been successfully addressed, as a small number of compounds targeting MYC are currently undergoing evaluation in clinical trials.

Introduction

The MYC family of genes that comprise C-MYC, N-MYC and L-MYC, are amongst the most frequently altered genes in human cancer [1–5]. Of these three paralogs, C-MYC (here after referred to as MYC) is the most frequently deregulated and is the best studied. Unlike most cancer-causing genes that tend to be altered by a single mechanism, such as mutation or amplification, MYC can be deregulated by diverse processes. These include amplification (mostly occur in epithelial tumours), translocation (mostly in leukaemia’s/lymphomas), increased oncogenic signalling which increases MYC expression and/or stability (most cancer types), enhancer activation, viral insertion (HPV in cervical cancer) and post-translational mechanisms such as loss of E3 ubiquitin ligases [3–6]. In contrast to many oncogenes/tumour suppressor genes, the protein coding sequence of MYC is rarely mutated in cancer, although such alterations have been detected in small numbers of specimens (< 1%) [7]. MYC mutations, however, have been found in up to 40% of Burkitt’s lymphoma [8]. Overall, MYC is believed to altered/deregulated, by one of the above mechanisms, in approximately 70% of all human malignancies [9].

Because of its high prevalence of deregulation, MYC is an attractive target for the new drugs to treat cancer. Development of effective anti-MYC therapies with clinical efficacy, however, has historically been difficult. The difficulties, however, appear to have been successfully addressed, as recently several compounds targeting MYC-dependent tumours commenced evaluation in clinical trials. The main aim of this manuscript is to review the current status of pharmacologically targeting MYC for cancer treatment. As several reviews have recently discussed the role of MYC in carcinogenesis [3–5], this topic is only briefly reviewed in our article.

Role of MYC in Cancer Formation

Evidence from a diverse range of animal model malignancies suggests that MYC is causally involved in tumour development, maintenance, progression and metastasis [3–5]. The cancer promoting effects of MYC stem primarily from its ability to regulate the expression of genes involved in several different pathways. In total, MYC is believed to regulate up to a third of the transcriptome [10]. To activate gene expression, MYC interacts with its obligate binding partner, MAX that is followed by the heterodimer preferentially attaching to the palindromic E-box sequence, CACGTC at promoter and enhancer sites across the genome [11]. Binding at promoter sites appears to induce the expression of similar genes across different cancer types. In contrast, binding to enhancer regions causes cancer-type specific gene expression (12). As well as upregulating gene expression, MYC can also represses transcription which in at least some situations is mediated by MYC binding to MIZ-1, SP1 or NF-Y [13–15]. To fine tune gene transcription, MYC complexes interact with multiple other transcription factors and regulatory proteins [11, 16].

Deregulated MYC is believed to promote cancer formation via both cancer cell intrinsic and extrinsic mechanisms (Tables 1 and 2; Fig 1) [3–5]. Tumour cell intrinsic effects include most of the cellular activities responsible for the hallmarks of cancer such as promoting cell cycle progression, enhancing tumour cell proliferation, altering metabolism, blocking DNA repair and increasing cell stemness [3–5].

Table 1.

Activities of MYC and their mediating genes involved in promoting cancer formation via cancer cell intrinsic effects

Activity	Genes/pathways
Increase tumour cell proliferation	↑ CDK, cyclins (cyclin A, D1, E), ↓ CDK inhibitors (p16, p21 and p27); ↑ E2F: ↑ DNA replication genes (minichromosome maintenance complex)
Alter metabolism	↑ Lipogenesis, glycolysis and glutaminolysis, ↓ oxidative phosphorylation, ↑ nucleotide synthesis
Enhance angiogenesis	↓ TSP-1, ↑ VEGF
Induce stem cell-like state	↑ Epigenetic reprogramming ↓ Lineage-specifying transcription factors ↑ WNT-pathway genes
Increase ribosomal biogenesis	↑ RNA Pol I–III-mediated rDNA transcription
Decrease senescence*	↑ Cyclins ↑ TERT ↓ p16 and p21

CDK cyclin-dependent kinases, TSP-1 thrombospondin, TERT telomerase reverse transcriptase, ↑ upregulation, ↓ downregulation Data summarized from Refs. [3–5] and references therein. MYC can induce or suppress senescence, depending on the cell context, i.e., in normal cells, MYC can activate oncogene-induced-senescence while in malignant cells, MYC can suppress senescence

Table 2.

Actions of MYC in different cancer types that may lead to suppression of host anti-tumour immunity

Immune effect	Cancer	Ref(s).
Promote efflux of CD3+ cells and influx of macrophages, MDSC, neutrophils, B cells	Pancreas	[19]
Promote efflux of T cells, influx of macrophages	Lung	[20]
Promote efflux of T cells	TNBC	[21-23]
Suppress inflammatory macrophages	Hepatocellular	[24]
↑ Production of PD-L1 + “don’t eat me signal” (CD47)	T-ALL	[25]
↓ MHC-1 production	Melanoma	[26-28]
Inhibition of interferon-gamma formation	TNBC	[21]
↓ STING production	TNBC	[29]
Prevent NK cell activation	Lymphoid	[30]
Alter metabolism	Multiple cancers	[31-33]
Alter glycosylation on tumour cell membrane	Leukaemia	[34]

MDSC myeloid derived suppressor cells, ↑ upregulation, T-ALL T cell acute lymphoblastic leukaemia, ↓ downregulation, TNBC triple-negative breast cancer, STING stimulator of interferon genes

Fig. 1.

Actions of MYC and their mediating genes involved in promoting cancer formation. For clarity, some details are omitted. *MYC can induce or suppress senescence depending on the cell context. For example, in normal cells, MYC may cause oncogene-induce senescence, thereby preventing carcinogenesis. During the formation of malignancy, MYC may block senescence, contributing to immortalization of pre-malignant or cancer cells. CDK, cyclin-dependent kinase; OP, oxidative phosphorylation; MP, macrophages, MDSC, myeloid-derived suppressor cells; NP, neutrophils; NK, natural killer cells; TSP-1, thrombospondin; TERT, telomerase reverse transcriptase; ↑, upregulation; ↓, downregulation Data summarized from refs. 3–5 and references therein

In addition to its tumour cell intrinsic effects, increasing evidence implicate MYC in altering the tumour microenvironment, especially by promoting immune evasion [3, 16–18]. These extrinsic effects of MYC appear to be accomplished using several different pathways (Table 2) which may vary from one tumour type to another. For example, activation of MYC in a model of indolent mutant KRAS pancreatic intraepithelial neoplasia resulted in rapid influx of macrophages, myeloid-derived suppressor cells, neutrophils and B cells but efflux of CD³⁺ T cells [19]. The influx of macrophages appeared to be mediated by CCL9 while the uptake of neutrophils appeared to be promoted by CXCL5 [19].

In contrast to the pancreatic cancer model, MYC caused an efflux of B cells in a lung cancer model. This expulsion of B cells appeared to be executed by Il23, a cytokine not detectable in the pancreatic model [20]. In mouse models of triple-negative breast cancer (TNBC), MYC activation also led to T cell efflux/decreased uptake by tumours [21–23], while in a model of hepatocellular cancer, MYC promoted tumour evasion via suppression of proinflammatory macrophages [24].

It is important to state that overexpression of MYC alone, rarely causes tumorigenesis. For the later to be achieved, MYC usually collaborates with other cancer driver genes, especially mutant KRAS [35, 36] or mutant TP53 (p53) [37, 38]. Despite this co-dependence on other altered genes, inhibition of MYC alone can induce anticancer responses (see below).

Targeting MYC for Cancer Treatment

Since MYC activation/overexpression drives cancer formation, inactivation or blocking its functioning would be expected to negate cancer growth and cause tumour regression.

Consequently, in recent years, there has been intensive research aimed at the discovery and pre-clinical testing of pharmacological anti-MYC treatments for cancer (Table 3) (for review, see refs. [39–44]. Many of the MYC inhibitors reported in the literature, however, are likely to lack specificity and potency for their target. Furthermore, with a few exceptions, most were investigated in only a single model system (for a recent review, see ref. 44). However, a small number have been extensively studied across different experimental systems. Importantly, at least five compounds targeting MYC-dependent tumours have recently progressed to clinical trials (see below). One of these has now completed evaluation in a phase I trial with sufficiently promising results to progress to further trials. As it is beyond the scope of this article to review all the MYC inhibitors described in the literature, we focus only on the compounds that have been widely studied and where confirmatory studies across multiple model systems have been reported. Firstly, we briefly discuss the multiple features that make MYC an attractive novel target for anti-cancer therapies.

Table 3.

Different types of inhibitors investigated for targeting MYC with specific examples

Inhibitor class	Drug
Peptides	Omomyc, OMO-103, IDP-121, DuoMYC, ME47
MYC-MAX antagonists	MYCi975, MYCi361, MYCMI-6, MYCMI-7, KJ-Pyr-9
MAX homodimer stabilizers	KI-MS2-008, NSC13728
MYC expression inhibitors	Omomyc, OMO-103
	JQ1, AZD5153
	QN1, APTO-253
	THZ1
	KB0742
	5-mer 5′-AACGTTGAGGGGCAT-3
	STR116, STR118,
MYC-WDR5 antagonists	WM662, C6
Exploiters of synthetic lethality	Purvalanol
	VX-680
	Olaparib
	NU-7441, KU0060648
Translational blockers	Silvestrol
Protein degraders	MRT-2359, WBC100
	MKI-1
	KPT-6566
	MLN8327
Oxidative phosphorylation inhibitors	IACS-010759

WDR5 WD Repeat-Containing Protein 5

List is not exhaustive. Data summarised from refs. 39–42

Why Target MYC for Cancer Treatment

MYC has multiple desirable features as a potential target for new anti-cancer treatments [39–42]. These attractive properties are briefly summarized below:

• Extensive evidence from animal model studies shows that deregulated MYC causes the formation and/or maintenance of cancer, while blocking or inactivating MYC leads to tumour regression

• Extensive deregulation of MYC occurs across diverse types of malignancy (aberration in up to 70% of cases)

• Since MYC promotes cancer formation via both cancer cell intrinsic mechanisms and suppressing immunity, inhibiting the oncogene would be expected to both decrease tumour cells growth and enhance host anti-tumour immunity

• As overexpression of MYC causes resistance to a wide range of anti-cancer drugs [45], inhibiting MYC should result in response to these drugs. This in turn might be expected to lead to enhanced and possibly synergistic growth inhibition

• As MYC is positioned downstream of multiple internal pro-oncogenic signalling systems [9, 46], its inhibition could potentially block several different pathways promoting tumour growth.

Difficulties in Targeting MYC

Despite the above-mentioned attractive features, there is currently no approved anti-MYC therapy for patients with cancer. Some of the reasons for this failure include:

• Monomeric MYC is largely an intrinsically disordered protein lacking deep stable hydrophobic active sites or allosteric pockets for high-affinity binding of potential low molecular weight inhibitors

• Since mutations in MYC are rare [7], development of mutant specific drugs is not possible

• The predominant nuclear location of MYC renders it difficult to target with high molecular weight drugs such as conventional monoclonal antibodies

• MYC’s large interaction surface area (in contrast to the considerable smaller catalytic crevices in enzymes) might be expected to limit the effectiveness of potential low molecular compounds in preventing binding to MAX or other interacting proteins

• MYC lacks enzyme activity, precluding inhibition with competitive catalytic inhibitors.

• As MYC is involved in several normal cellular activities, avoiding severe toxicity due to its inhibition is imperative but might be expected to be difficult.

On the basis of recent reports, many of the above problems appear to have been successfully resolved and the previous pessimism associated with targeting MYC seems to be passing, as illustrated below.

Promising MYC Inhibitors Based on Preclinical Studies

Although several putative MYC inhibitors have been described, only two, i.e., Omomyc and MYCi975 have been subjected to detailed preclinical investigations. Here, we summarise the key finding, reported to date, with these anti-MYC compounds.

Omomyc

One of the best investigated MYC inhibitors is the dominant-negative MYC polypeptide, known as Omomyc. Omomyc, which was originally discovered in 1998, is a 11 kDa, 91 amino acid mutant polypeptide based on the helix-loop-helix leucine zipper domain in MYC [47]. To modify its dimerization specificity, four amino acid residues were substituted in the leucine zipper sequence [47]. Omomyc has multiple modes of action enabling it to act as an anti-cancer therapy [47–52]. Although preventing interaction of MYC with its cognate binding partner, MAX, Omomyc homodimerizes with itself and heterodimerizes with both MYC and MAX. MYC-Omomyc heterodimers are unable to bind to E box consensus DNA regions but importantly, block MYC from binding. Omomyc homodimers and Omomyc-MAX heterodimers, however, can attach to DNA but are unable to activate transcription. Consequently, MYC-MAX gene regulation is blocked (Fig. 2a) [47–50].

Fig. 2.

Mode of action of OmoMYC and MYCi975 as anti-cancer agents. a OmoMYC. OmoMYC blocks the interactions between MYC and MAX (based on PDB 6G6K). This leads to the formations of OmoMYC homodimers (based on PDB 5i50), OmoMYC-MYC heterodimers and OmoMAX heterodimers. OmoMYC heterodimers are unable to bind to DNA and are thus inactive in altering gene expression. Both OmoMYC homodimers and OmoMYC-MAX heterodimers bind to E-box regions in DNA but are transcriptionally inactive. b MYCi975. MYC functions by forming heterodimers with MAX. MYCi975 blocks this heterodimerization which subsequently leads to MYC T58 phosphorylation and degradation of MYC (based on PDB 6G6K). OM, OmoMYC

Multiple preclinical studies show that treatment with Omomyc inhibits cancer cell growth and leads to tumour regression. This reduction in cancer cell growth has been reported in a wide range of different animal model systems, including models of lung cancer [51], melanoma [52], TNBC [53], glioblastomas [54], and pancreatic cancer [19]. Consistent with the dual ability of MYC to promote carcinogenesis via both cancer cell intrinsic and cell extrinsic processes, treatment with Omomyc was shown to exert both direct anti-cancer effects on tumour cells and to alter the tumour microenvironment. For example, in a model of NSCLC, treatment with Omomyc inhibited tumour cell growth and increased uptake of CD3⁺ T lymphocytes [51]. Similarly, in models of TNBC, administration of Omomyc reduced cancer cell proliferation, promoted apoptosis, blocked angiogenesis and reduced the formation of metastasis [53], while a phylomeric form of Omomyc decreased levels of the negative immune regulator protein, PD-L1 [55]. These finding clearly show that Omomyc can mediate both direct effects on cancer cells as well as on the immune system. Recently, a form of Omomyc known as OMO-103 was evaluated in an open label, phase 1 clinical trial (see below).

As MYC regulates the expression of a large number of genes and is involved in several normal cellular processes, its inhibition might be expected to have major toxicity. Surprisingly, however, in the models tested to-date, administration of Omomyc appeared to cause minimal toxicity [49, 53, 54, 56]. The minimal toxicity may relate to a therapeutic window resulting from different expression levels of MYC in normal and malignant tissue. Thus, in normal non-proliferating tissue, MYC is rapidly degraded with a half-life of < 30 min. In contrast, as mentioned above, MYC expressions is deregulated/overexpressed in most malignancies.

Although mini proteins/peptides, such as Omomyc, are potentially more specific inhibitors for MYC than low molecular weight compounds [57], such molecules may be more susceptibility to degradation in vivo [58]. However, early studies in mice using labelled Omomyc suggested that the peptide had a surprisingly long half-life, i.e., > 60 h in plasma [51]. More recent studies using label free Omomyc found that the peptide penetrated into tumours within 2 h of administration, entered the cell nucleus and persisted in the tumour for at least 72 hr [59]. This relatively long half-life may relate to Omomyc being present in a dimeric rather that in a monomeric form [59].

To enable Omomyc more selectively target specific types of cancer cells, Bibbo et al. [60] conjugated the peptides to an anti-HER3 monoclonal antibody (EV50). The antibody drug conjugate (ADC), dubbed EV20/Omomyc, was found to decrease the formation of metastasis in a mouse model of HER3-positive neuroblastoma. Further results with this antibody conjugated are eagerly awaited.

MYCi975

MYC-MAX low molecular antagonists are the most widely investigated experimental class of MYC inhibitors [39–42]. Within this class, MYCi975 (4'-chloro-6-((4-chlorobenzyl)oxy)-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-3'-(trifluoromethyl)-[1,1'-biphenyl]-2-ol) is perhaps the most widely studied [61–69]. MYCi975 and the related analog, MYCi361 block MYC-MAX heterodimerization by binding to MYC at amino sequence 366-381 in the helix-loop-helix domain (Fig. 2b) [61]. This sequence of amino acids is enriched in hydrophobic residues and has been postulated to exist in a transient secondary structure [64]. Further to antagonizing the interaction between MYC and MAX, treatment with MYCi975 led to increased phosphorylation on the tyrosine 58 (T58) residue of MYC that in turn led to its degradation by the 26S proteasome system (Fig. 2b) [61].

MYCi975 has been shown to inhibit cell proliferation in mouse models of prostate cancer [61], breast cancer [65], head and neck cancer [66, 67], as well as leukaemia cells [68]. In the prostate cancer mouse model investigated, MYCi975 was reported to display excellent pharmacokinetic properties, irrespective of the mode of delivery, i.e., whether by intravenous, intraperitoneal or per-oral routes [61]. Depending on dose delivered, the half-life was found to vary between 7 and 12 h. Treatment with MYCi975 altered chromatin binding of MYC and modulated gene expression (63). While genes involved in pathways associated with cell cycle progression, chromosome organization, DNA repair and DNA replication showed decreased expression, genes involved in signal transduction pathways were increased. Genes implicated in RNA biogenesis or core transcriptional activities, however, were not significantly altered by MYCi975.

Similar with Omomyc and consistent with the reported abilities of MYC to promote tumour growth via both tumour cell intrinsic and extrinsic mechanisms (see above), treatment with MYCi975 was found to alter the immune cell composition in the tumour microenvironment. Thus, administration of MYCi975 to a mouse model of prostate cancer resulted in increased uptake of CD3⁺ T lymphocytes, B lymphocytes and NK cells [61]. Furthermore, treatment with MYCi975 produced an increase in PD-L1 levels in the tumour microenvironment, while combined treatment with MYCi975 and immunotherapy with an anti-PD-1 antibody led to synergistic growth inhibition [61]. Similarly, in mouse models of TNBC [22] and head/neck cancers [66], administration of MYCi975 altered the tumour microenvironment by increasing infiltration of CD8⁺ T cell. In the TNBC model, combined treatment with MYCi975 and the anti-PD-L1 antibody, atezolizumab suppressed growth of a TNBC model more strongly than either therapy alone [22]. This enhanced/synergistic growth inhibition caused by these combined treatments was probably owing to a combination of tumour intrinsic and extrinsic anti-tumour effects mediated by MYCi975.

In addition to synergizing with immunotherapy in the prostate cancer model mentioned above, co-treatment with MYCi975 and either doxorubicin or paclitaxel in breast cancer cells [65] or with enzalutamide in prostate cancer cells [61], also resulted in enhanced growth inhibition.

Again, similar with Omomyc, MYCi975 was reported to exhibit little toxicity in the animal model systems investigated [61, 63]. In particular, MYCi975 did not affect blood biochemistry analytes, kidney or liver function tests. Furthermore, gross and histological examination of multiple organs, including liver, kidney, brain, heart, lung and spleen, suggested no evidence of toxicity. Indeed, doses of MYCi975 up to 1000 mg/kg, which was considerably higher than that shown to have a therapeutic benefit in the prostate cancer model mentioned above, were found to cause few side effects [61]. MYCi975 or an optimized version of the molecule may soon commence evaluation in a clinical trial [69].

MYC Inhibitors in Clinical Trials

At least five anti-MYC compounds are now undergoing testing in early clinical trials (Table 4). The first directly acting MYC inhibitor to undergo and complete such a trial was the Omomyc-related compound, OMO-103 [70]. OMO-103 was initially tested in an open label phase I clinical trial in 22 patients with diverse types of previously treated advanced cancers [70]. Despite being a peptide, the half-life of OMO-103 in sera was estimated to be approximately 40 h. Furthermore, using mass spectrometry, OMO-103 was detectable in patient biopsy samples up to 19 days following the infusion. Overall, the treatment was well tolerated, the most frequent adverse effect being grade 1 infusion-related events which occurred in 10 patients. Of the 19 patients evaluable for response, 8 had stable diseases as determined by computed tomography. Evidence of target engagement by OMO-103 was the finding of decreased MYC transcriptional activity which appeared to correlate with stable disease. Consistent with MYC’s ability to suppress immunity, treatment with OMO-103 increased the expression of immune response-related genes including genes implicated in T-cell mediated immunity. OMO-103 in combination with chemotherapy is currently being tested in an open-label, multicentre, phase Ib trial in patients with metastatic pancreatic cancer (ClinicalTrials.gov ID, NCT06059001) and in a phase II trial in patients with advanced high-grade osteosarcoma (NCT6650514).

Table 4.

Drugs undergoing clinical trials for the treatment of MYC-dependent tumours

Compound	Mechanism of action	Company	NCT	Trial phase
OMO-103	Peptide that suppresses expression of MYC	Peptomyc S.L.	NCT06059001, NCT06650514	Ib/II
WBC100	MGD	Weben Pharma	NCT05100251	I
MRT-2359	MGD	Monte Rosa Therapeutics	NCT05546268	I/II
KB-0742,	CDK9 inhibitor, (decreases expression of MYC)	Kronos Bio	NCT04718675	I/II
IDP-121	Stapled peptide that disrupts MYC-MAX interaction	IDP Pharma	NCT05908409	I/II

MGD molecular glue degrader, NCT ClinicalTrials.gov Identifier, CDK9 cyclin-dependent kinase. 9

In addition to OMO-103, 2 molecular glue degraders targeting MYC are in clinical trials. One of these, i.e., WBC100 (14-D-Valine-TPL) (Fig. 3a) is undergoing evaluation in patients with advanced solid tumour expressing c-MYC (NCT05100251). WBC100 acts by binding to the nuclear localization signal 1 (NLS1)–basic–NLS2 region of MYC and inducing its degradation via the ubiquitin E3 ligase CHIP-mediated proteasome system [71]. WBC100 was found to exhibit anti-cancer activity in mouse models of pancreatic cancer and leukaemia. As with the other MYC inhibitors mentioned above, WBC100 was reported to be well tolerated in the model systems tested at doses exhibiting tumour regression. Preliminary clinical findings with WBC100 were recently reported [72]. Of 28 patients treated, 6 (21%) were described as experiencing grade 3 or higher treatment-related adverse events. Of 19 patients evaluable for possible efficacy, one (5.3%) showed partial regression, and six (31.6%) had stable disease.

Fig. 3.

Structure of the molecular glues a WBC100 and b MRT-2359

Another molecular glue undergoing clinical trials for the treatment for MYC-dependent tumours in MRT-2359 (Fig. 3b). This compound acts by promoting interaction between the E3 ubiquitin ligase cereblon and the translation termination proteins, GSPT1/GSPT2 [73, 74]. This leads to degradation of GSPT1/2 and cessation of protein synthesis. According to Gavory et al. [73], MYC-dependent cancers are addicted to protein translation and consequently are dependent on GSPT1 functioning. Consistent with this rationale, in vitro and in vivo preclinical studies showed that MRT-2359 exhibited superior anti-cancer activity in high MYC expressing tumours than in low MYC expressing tumours [73, 74]. MRT-2359 is currently being evaluated in a phase I/II open-label, multicentre trial in patients with diverse tumour types exhibiting L-MYC or N-MYC gene amplification (NCT05546268).

Other anti-MYC inhibitors undergoing evaluation in clinical trials include the stapled peptide IDP-121 (IDP Pharma) which acts by disrupting MYC-MAX interaction (NCT05908409) [75] and the CDK9 inhibitor, KB-0742 (Kronos Bio, Inc) which downregulates MYC expression (76). No update appears to be available on the IDP-121 clinical trial. Preliminary evidence from an ongoing phase I/II study (NCT04718675) with KB-0742 suggests that the compound is well tolerated [77].

Conclusions

Although discovered over 40 years ago and having approximately 50,000 publications listed in PubMed, we may finally be on the brink of establishing if targeting MYC has therapeutic value in patients with cancer. As the ongoing trials progress, it will be important to address the following:

• identify and validate biomarkers that predict response to anti-MYC compounds

• establish if the anticancer efficacy of anti-MYC compounds can be improved by combination with the established anti-cancer agents

• establish if long-term treatment with anti-MYC compounds cause serious adverse effects

• determine if compounds that act by blocking MYC-MAX dimerization also inhibit the interaction between MYC and MIZ-1

• identify more precisely the mode of action of anti-MYC compound, especially specificity of the indirect-acting inhibitors.

Further future work should also investigate the new artificial intelligence tools, such as AlphaFold [78] and PocketMiner [79], with the aim of identifying potential previously unrecognized pockets in MYC. This in turn may enable the identification of new potent and specific inhibitors for MYC. Other areas for future work should include the targeting MYC mRNA, with the aim of developing inhibitors against this form of MYC [80] and the use of cell permeable nanobodies capable of targeting nuclear MYC [81]. Finally, although the emerging results with MYC inhibitors suggests minimal toxicity, it is important to remember that we still have only short/relatively short-term treatment data. While this is encouraging, caution will be required with longer term therapy. In this context, it is important to mention that a recent report showed that postnatal elimination of MYC in mice caused premature aging and the deterioration of several age-related body functions [82].

With the multiple ongoing clinical trials, we should soon have answers to many of the long-standing questions regarding the targeting of MYC for cancer treatment. Most important, we should soon know if targeting MYC-dependent tumours has clinical efficacy with acceptable toxicity.

Funding

Open Access funding provided by the IReL Consortium.

Declarations

Funding

Cancer Clinical Research Trust.

Competing Interest

MJD and MT, no conflicts of interest. JC: Research funding (to institution): Eisai, Puma Biotechnology, Roche, Boehringer Ingelheim; Employment: OncoMark, Ltd.; Honoraria: Eisai, Puma Biotechnology; MSD Oncology, Pfizer, G1 Therapeutics; Novartis; Speaker’s Bureau: Boehringer Ingelheim, Genomic Health, Roche, Pfizer; Shares: OncoMark Ltd; Travel and accommodation expenses: Pfizer, MSD, Abbvie, Astrazeneca, Novartis.

Ethical Approval

Not applicable.

Informed Consent Statement

Not applicable.

Data availability

Not applicable.

Authorship Contributions

M.J.D. conceptualized and drafted the original version of the manuscript. M.T. and J.C. revised the manuscript with J.C. making a specific contribution to the clinical aspects discussed in the manuscript. All authors have read and agreed to the published version of the manuscript.