Breaking the bonds: targeting protein dimerization for prostate cancer therapy

Abstract

Metastatic prostate cancer (PCa) remains a major cause of cancer deaths in western men. Although androgen deprivation therapy (ADT) initially induces remissions, patients ultimately develop uncurable castration resistance, underscoring the need for alternative or complementary therapeutic strategies. Protein–protein interactions (PPIs) play a central role in oncogenic signaling, and aberrant protein dimerization is increasingly recognized as a critical driver of PCa progression and therapeutic resistance. Both homodimeric and heterodimeric protein complexes regulate key pathways involved in androgen receptor signaling, transcriptional control, and adaptation to tumor microenvironmental stress. Here, we review current evidence for oncogenic dimerization events in PCa and discuss their relevance for PCa progression. We highlight how similar dimeric interactions have been successfully targeted for therapy in other malignancies, with several strategies advancing to late-stage clinical trials or regulatory approval, underscoring their translational potential for PCa. We summarize approaches to modulate dimerization and highlight their mechanisms of action, therapeutic advantages, and inherent limitations. By combining pre-clinical and clinical findings with conceptual therapeutic frameworks, this review outlines the opportunities and limitations of targeting protein dimerization in PCa. Collectively, we propose that rational disruption of oncogenic homo- and heterodimers represents an underexplored yet promising therapeutic strategy that could complement existing treatments and help overcome resistance in advanced PCa.

1. Introduction: Treatment failure in advanced PCa underscores the need for novel therapeutic strategies

Prostate cancer (PCa) is the most frequently diagnosed cancer and the second leading cause of cancer-related death among American men [1, 2]. Since 2014, American PCa incidence has been increasing, while the decline in mortality has slowed [1, 2].

PCa development is accompanied by a dysregulation in signaling by the androgen receptor (AR), a ligand-activated transcription factor. AR signaling is essential for maintaining normal prostate physiology [3]. Prostate carcinogenesis is characterized by a shift in the AR cistrome resulting in the expression of transcriptional program that drives PCa progression [4]. The dependence of PCa cells on AR signaling serves as the basis for androgen deprivation therapy (ADT), the default treatment for non-organ-confined PCa [5]. ADT lowers circulating androgen levels or blocks androgen-AR interactions. Historically, ADT was achieved by surgical castration, but modern approaches use pharmacological agents such as gonadotropin-releasing hormone (GnRH) agonists and antagonists that inhibit testicular testosterone production, as well as antiandrogens that compete for AR binding [5]. Although ADT initially reduces PCa growth, resistance eventually develops through multiple mechanisms that reactivate AR signaling [5, 6]. The castration-resistant PCa (CRPC) that emerges under ADT and continues to rely on aberrantly re-activated AR has led to the development of more potent forms of ADT, and today includes combinations of multiple ADT agents or ADT combined with other treatments such as chemotherapeutics (e.g. docetaxel) [5, 7, 8]. While these treatments initially induce remissions, patients eventually develop resistance that remains driven by AR (CRPC) while in a minority, recurring PCa becomes AR-indifferent (neuroendocrine PCa, NEPC) [8, 9]. This reality underlines the need for novel therapeutic strategies beyond traditional suppression of the AR signaling axis. One promising area is targeting functional protein-protein interactions (PPIs), which are integral to carcinogenesis, transcriptional activation of oncogenes and drug resistance [10, 11].

The goal of this review is to explore the potential of preventing PPIs, and specifically protein dimerization events, as novel treatment strategy to delay PCa progression and overcome treatment resistance.

2. Protein dimerization as a therapeutic target in cancer

PPIs are important for nearly every cellular process. A PPI constitutes a complex process with many factors contributing to its stability such as complementary interfaces, hydrophobic interactions, formation of hydrogen bonds, and salt bridges [12]. PPIs affect not only enzymatic activities and signaling but also regulate spatial-temporal protein location, substrate selection, protein interactomes and transcriptional outcomes. This review focuses on one aspect of PPIs: protein dimerization, which is interaction between two proteins. Dimers can either be homodimers (identical monomer pairing) or heterodimers (distinct partner pairing). Dimer interactions can be transient or stable, induced by ligands or post-translational modifications or constitutive, symmetric or asymmetric, nuclear or cytoplasmic or both (Figure 1) [13]. Homodimers usually stabilize protein conformations and increase their binding affinity. For example, AR requires homodimerization to bind to androgen response elements (AREs) in target genes [14]. Heterodimers sometimes create new functions that are not present in either monomer [13, 15]. For instance, HER2 harbors high catalytic potential and HER3 contains multiple PI3K binding sites but no catalytic activity, but HER2:HER3 heterodimers form a strong signaling complex that robustly activates PI3K-AKT signaling [16, 17].

Figure 1. Protein dimerization and its regulatory and cellular consequences.

Dimerization of individual proteins (protein I and protein II) is induced by ligand-binding or post-translational modifications or proteins may undergo constitutive dimerization. Proteins form homodimers (protein I-protein I) or heterodimers (protein I-protein II) depending on cellular context and regulatory signals. Dimerization can alter protein conformation, stability, and cellular consequences, as outlined below. (A) Dimerization can modulate protein’s catalytic function, resulting in either activation or inhibition of enzymatic activity. Both homo- and heterodimers may generate distinct functional states compared to monomers. (B) Dimer formation can stabilize proteins by shielding degradation motifs or, alternatively, destabilize them by exposing ubiquitination sites. In some cases, stable dimers coexist with unstable monomers, whereas in others, monomeric proteins are stable, and dimerization is transient. (C) Dimerization can influence intracellular trafficking and compartmentalization by promoting nuclear import, cytoplasmic retention, or membrane association by revealing or masking localization signals. (D) Formation of dimers can rewire the protein interactome by creating new binding surfaces. (E) Dimerization of transcription factors can control promoter binding, transcriptional activation or repression, and downstream signaling outputs, leading to distinct gene expression and cellular responses. The figure was generated using Biorender.

Cancer cells exploit dimerization to co-ordinate cellular decisions in their favor, by evading normal control of cell growth. Oncogenic complexes such as BCR-ABL, EGFR-HER2, and MYC-MAX dimers illustrate that alterations in PPIs promote malignancy [18–20]. Targeting PPI interfaces, rather than catalytic sites, has emerged as a promising therapeutic strategy [21–23]. However, while enzymes have well-defined catalytic pockets, PPIs often harbor large and flat interaction surfaces [24], leading to the perception that PPIs are undruggable targets [25]. Now, advances in structural biology, computational modeling, and high-throughput screening have facilitated the identification of hot spots within these large interaction surfaces that are critical for maintaining PPIs and can be targeted by small molecules, peptides, engineered peptides, peptidomimetics, and monoclonal antibodies [24, 26, 27]. Compounds that disrupt oncogenic dimerization are entering advanced clinical trials and have demonstrated both efficacy and tolerability with some already regulatory approved [11, 28, 29].

3. Emerging dimerization targets in PCa

Several of these dimerization events are also critically involved in PCa progression and treatment resistance. Many signaling events involved in the progression of advanced PCa, including AR, MYC, STAT3, and BCL-2 family members, rely on dimerization. These dimeric interactions create structural dependencies that could be therapeutically used in PCa. While targeting dimerization of proteins has gained attention across oncology, its role in PCa progression and treatment resistance has not been clearly determined. In this review, we highlight representative dimerization-dependent pathways in PCa to illustrate shared biological principles, emerging therapeutic strategies, and remaining translational challenges.

3a. HER2:HER3 heterodimers

HER2:HER3 heterodimers represent one of the most powerful oncogenic signaling pairs, activating the PI3K-AKT pathway (Figure 2A). HER2 and HER3 are frequently overexpressed in CRPC, where HER2:HER3 dimerization mediates AR activation under ADT and increases AR protein stability and DNA-binding, thus promoting CRPC growth [30, 31]. Pertuzumab is a humanized monoclonal antibody that binds to the extracellular domain II “dimerization arm” of HER2, thereby blocking HER2’s dimerization with HER3 or HER2 and preventing downstream signaling [32]. Pertuzumab is approved for HER2-positive breast cancer [33, 34]. Lapatinib, another FDA-approved HER2 inhibitor for breast cancer [35], has shown single agent activity in a small subset of CRPC patients [36]. Amiloride drives HER3 from the nucleus to the cytoplasm and increases its availability for HER2:HER3 dimerization that could be effectively inhibited by lapatinib. This combination suppressed downstream signaling more strongly, suggesting a repurposed neoadjuvant strategy for PCa [37]. Zenocutuzumab (MCLA-128) is a bispecific HER2×HER3 antibody, evaluated in the NCT04100694 trial, which enrolled patients with NRG1 fusion-positive solid cancers, inclucing PCa, that has been FDA-approved for advanced, unresectable, or metastatic non-small cell lung cancer (NSCLC) and pancreatic adenocarcinoma harboring a NRG1 gene fusion. The HER2-targeted antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-DXd/Enhertu) is in phase II trials for HER2-positive mCRPC patients (NCT06610825).

Figure 2. Therapeutic targeting of oncogenic heterodimerization in cancer.

Representative oncogenic signaling pathways in which heterodimer formation. (A) Ligand-induced heterodimerization between members of the ERBB receptor tyrosine kinase family, particularly HER2–HER3, drives potent downstream signaling through the RAS-RAF-MEK-ERK, PI3K-AKT, and JAK-STAT pathways. This generates stronger and sustained oncogenic signals promoting survival, proliferation, cell-cycle progression, inflammation, metastasis, and angiogenesis. Therapeutic strategies targeting HER heterodimers can block kinase activation and prevent downstream signals. (B) Under normoxic conditions, HIF-α subunits are hydroxylated and targeted for proteasomal degradation via the VHL complex. In hypoxia, stabilized HIF-1α or HIF-2α forms obligate heterodimers with HIF-1β (ARNT), translocates to the nucleus, and binds hypoxia-response elements (HREs) to activate transcriptional programs that promote angiogenesis, metabolic reprogramming, survival, and invasion. Disrupting HIF-α/β heterodimerization represents a strategy to selectively suppress hypoxia-driven tumor adaptation. (C) The oncogenic transcription factor MYC requires heterodimerization with MAX to bind E-box DNA elements and activate gene expression programs controlling cell cycle progression, DNA damage repair, metabolism, angiogenesis, and proliferation while suppressing differentiation. Inhibition of MYC-MAX dimerization blocks oncogenic transcriptional output and reduces tumorigenesis. (D) The tumor suppressor p53 is negatively regulated through heterodimeric binding to the E3 ubiquitin ligase MDM2, which promotes p53 ubiquitination and proteasomal degradation. Disruption of the p53-MDM2 interaction stabilizes p53, restores transcription of p53 target genes, and reactivates tumor suppressive responses such as cell-cycle arrest and apoptosis. (E) Anti-apoptotic BCL-2 family members (BCL-2, BCL-XL, MCL-1) form heterodimeric complexes with pro-apoptotic BH3-only proteins and effector proteins (BAX, BAK), thereby preventing mitochondrial outer membrane permeabilization. Disruption of these heterodimers releases BAX/BAK, induces cytochrome c release, activates caspases, and triggers apoptosis in cancer cells. The figure was generated using Biorender.

3b. HIF-α: ARNT heterodimers

Hypoxia-inducible factor α (HIF-α) and its partner aryl hydrocarbon receptor nuclear translocator (ARNT, aka HIF-1β) represent another heterodimeric complex (Figure 2B) implicated in the progression and therapy resistance of several cancers, including PCa [38]. HIF-2α is frequently overexpressed in PCa and correlates with higher Gleason score and grade, suggesting a role in PCa aggressiveness [39]. HIF signaling interferes with the AR pathway in a context-dependent manner, influencing PCa adaptation under metabolic and hypoxic stress. HIF activation co-operates with AR and modulates AR target gene specificity. Hypoxia enhances AR activity by promoting AR nuclear translocation, ARE-binding, and heightens sensitivity to low androgen levels [40]. HIF-1α and HIF-2α expression in PCa strongly correlate with AR and VEGF levels, linking hypoxia signaling to androgen-driven angiogenesis and suggesting that dual pathway inhibition as a therapeutic strategy in androgen-sensitive PCa [41]. Hypoxia-mediated AR sensitization likely contributes to treatment resistance and recurrence following ADT [40, 42] while dual targeting of AR and HIF signaling enhances apoptosis and overcomes resistance when HIF-1α or HIF-2α are inhibited alongside with enzalutamide treatment in CRPC [43].

Designing inhibitors directly targeting HIF-α subunits has been challenging because of the absence of conventional druggable pockets. Structural studies revealed a hydrophobic pocket in the PAS-B domain of HIF-2α that mediates its heterodimerization with HIF-1β/ARNB, providing a druggable interface for targeted heterodimerization inhibition. Early inhibitors such as THS-044 and several optimized benzoxadiazole derivatives selectively inhibited HIF-2α function but showed limited in vivo efficacy due to structural flexibility and suboptimal pharmacokinetics [44]. Further optimization led to PT2385 [45] and subsequently to its metabolically improved version PT2977 (Belzutifan). Belzutifan binds directly to the PAS-B pocket, preventing ARNT association with HIF-2α and thereby suppressing transcription of hypoxia-responsive genes [46]. Belzutifan is approved as monotherapy for von Hippel–Lindau disease-associated renal cell carcinoma (RCC), central nervous system hemangioblastomas, or pancreatic neuroendocrine tumors, and for advanced clear-cell RCC following prior PD-1/PD-L1 and VEGF-targeted therapies [45]. A more potent derivative, casdatifan, is in phase I trials for RCC as well as advanced solid cancers lacking other treatment options (NCT05536141, NCT07011719). Beyond small molecules, a SICLOPPS-based cyclic peptide screen identified cyclo-CRLII(4-iodo)F, which binds both HIF-1α and HIF-2α PAS-B domains, disrupts their interaction with HIF-1β, and suppresses hypoxia-driven signaling across cancer models [47]. Clinically, HIF-2α inhibition is being explored in PCa. The KEYNOTE-365 trial includes a cohort evaluating belzutifan and belzutifan plus pembrolizumabin in (docetaxel-pretreated) metastatic CRPC (mCRPC) (NCT02861573).

3c. MYC: MAX heterodimer

MYC is a central regulator of cell growth, metabolic reprogramming, and survival, and is overexpressed in advanced PCa where it drives disease progression, treatment resistance and lineage plasticity that causes NEPC [48]. Its oncogenic activity depends on heterodimerization with its partner MAX (Myc-associated factor X), forming a functional DNA-binding complex that binds promotors of target oncogenes (Figure 2C) [48]. Thus, disruption of MYC-MAX dimerization represents a rational strategy to inhibit MYC-driven transcription in PCa.

Despite being considered “undruggable” due to its intrinsically disordered structure and lack of enzymatic activity, multiple approaches have shown that MYC-MAX interactions are pharmacologically targetable. Small molecules such as 10058-F4 and related derivatives (10074-G5, and 10074-A4) provided early proof-of-concept that disruption of MYC-MAX binding suppresses proliferation and induces apoptosis in MYC-dependent cancers, although with limited in vivo stability. Additionally, several other small-molecule inhibitors, including Mycro3, 3JC48–3, KJ-Pyr-9, sAJM589, and MYCMI-6, have demonstrated antiproliferative activity across MYC-dependent cancer models, further reinforcing the broader therapeutic relevance of targeting MYC-MAX in PCa [49, 50] [51] [52] [53] [54, 55]. Recently, structure-based virtual screenings of compounds identified VPC-70063 as a potent and selective inhibitor that reduces Myc-Max DNA-binding, suppresses Myc-mediated pathways in PCa cells, reduces levels of the ADT-induced constitutively active AR variant 7 (AR-V7), inhibits proliferation in Myc-positive cells, and induces apoptosis with minimal toxicity. VPC-70619, a related N-Myc inhibitor also demonstrated potent transcriptional inhibition and strong activity in NEPC models with high oral and intraperitoneal bioavailability [56]. OMOMYC, a miniprotein that forms inactive dimers with MYC and MAX, [57] showed preliminary evidence in C4–2B cells suggesting this approach can directly target c-MYC and can be considered for mCRPC and NEPC [58]. OMO-103, based on Omomyc, has progressed into first-in-human phase I clinical trials patients with advanced solid cancers. The trial showed a favorable safety profile with mild adverse effects and early signs of anti-tumor activity, including cancer shrinkage and disease stabilization in a proportion of patients [59]. The identified predictive and pharmacodynamic signatures are currently being tested in a new clinical study for metastatic pancreatic cancer combining OMO-103 with standard-of-care chemotherapy (NCT06059001).

3d. MDM2–p53 heterodimer

Murine double minute 2 (MDM2) is an E3 ubiquitin ligase that forms heterodimeric complexes with the tumor suppressor p53, leading to p53 ubiquitination and proteasomal degradation. In normal cells, MDM2-p53 interaction is part of an autoregulatory feedback loop where p53 activates transcription of MDM2, and MDM2 in turn inhibits p53 activity (Figure 2D) [60], which is critical for maintaining cellular homeostasis but its deregulation is well-documented in oncogenesis. Approximately 50% of cancers harbor loss-of-function p53 mutations [61] while others overexpress MDM2 or other negative regulators of p53 [62]. MDM2 overexpression results in degradation of p53, and thus uncontrolled proliferation and survival of cancer cells [63, 64]. MDM2 overexpression is often mutually exclusive with p53 mutation, suggesting that cancers either mutate p53 or upregulate MDM2 to silence the p53 pathway [65, 66]. This makes the MDM2–p53 axis an attractive therapeutic target in cancers that retain wild-type p53 as inhibiting MDM2-p53 dimerization reactivates p53, which could triggers cell-cycle arrest, apoptosis and cancer regression [67, 68].

In early-stage PCa, p53 mutations are uncommon, but MDM2 overexpression occurs in about 30–40% of cases [69], which correlates with higher cancer grade, increased proliferation, and larger PCa volumes [70]. However, as PCa progresses to CRPC, p53 mutations become more frequent. Some CRPCs exhibit deregulated p53 signaling despite having an intact wild-type p53, due to aberrant overexpression of MDM2 [71]. In CRPC models that retain wild-type p53, targeting the MDM2-p53 axis has shown preclinical success. The MDM2 inhibitor XR-2 had significant anti-tumor activity in CRPC cell lines and xenograft models, where it not only induced p53-dependent apoptosis but also synergized with enzalutamide to overcome ADT resistance [72]. These findings suggest that dual targeting strategies, disrupting both MDM2-p53 interaction and AR signaling, can counter resistance mechanisms in mCRPC [73]. Nutlin-3 is a small-molecule antagonist of the MDM2-p53 interaction. In preclinical studies, nutlin-3 and related compounds showed reactivation of p53 in cancers that retained wild-type p53, induced growth arrest and apoptosis in various cancer models, leading to cancer regression. In LNCaP cells (which carry wild-type p53) under androgen-deprived conditions, nutlin-3 increased apoptotic cell death and downregulated AR levels. Combining ADT and nutlin-3 led to significant cancer regression and improved survival in LNCaP xenografts compared to ADT alone [73]. Similarly, the small-molecule inhibitor MI-219 sensitized wild-type p53 PCa cells to both radiation and bicalutamide treatment, enhancing treatment efficacy [74]. Several MDM2 inhibitors have advanced into clinical trials for other cancers such as RG7112, RG7388 (idasanutlin), AMG-232 (KRT-232), DS-3032b (milademetan), HDM201 (siremadlin), APG-115 (alrizomadlin). Most of these were designed to fit in the p53-binding pocket of MDM2 [75–77]. Ongoing trials focus on solid tumors with intact p53, and some include advanced PCas as part of broader eligibility criteria [75, 77]. The preclinical evidence provides a compelling proof-of-concept that targeting the MDM2–p53 heterodimer, alone or in combination with ADT, could overcome treatment resistance in p53-wild-type PCas.

3e. BCL-2 heterodimer

The BCL-2 protein family regulates the intrinsic apoptosis pathway by forming a dynamic network of PPIs [78]. BH3-only proteins (e.g. BIM, PUMA, NOXA) sense cellular stress and activate pro-apoptotic effectors (BAX and BAK), which dimerize and oligomerize at the mitochondrial outer membrane, triggering apoptosis. Anti-apoptotic members (BCL-2, BCL-XL, MCL-1) prevent unnecessary cell death by sequestering either BH3-only activators or BAX/BAK, thereby preventing apoptosis (Figure 2E) [79]. Cancer cells frequently overexpress anti-apoptotic proteins and exploit these pro-survival heterodimeric interactions, creating a dependency that can be therapeutically targeted [79, 80]. This dependency becomes increasingly relevant during CRPC progression. In ADT-naïve PCa, BCL-2 expression is usually low because AR suppresses BCL-2. During ADT, loss of AR activity enables the cancer cells to upregulate BCL2 that supports CRPC growth [81–84]. BCL-2 is further enriched in NEPC and correlates with poor prognosis. mCRPC patients with high BCL-2 had shorter overall survival than those with low BCL-2 [85].

Therapeutic inhibition of BCL2-BH3 interaction has been most successful using BH3 mimetics; small molecules that occupy the hydrophobic groove of BCL2, displacing pro-apoptotic BH3-only proteins. The most clinically advanced mimetic, venetoclax (ABT-199), is an orally bioavailable highly selective inhibitor approved for chronic lymphocytic leukemia and certain acute myeloid leukemias [86, 87] and is undergoing clinical trials for other cancers. In mCRPC, Venetoclax combined with enzalutamide (NCT03751436), showed an acceptable safety profile. However, enzalutamide induced strongCYP3A activity, reduced venetoclax exposure by 2–3-fold, leading to modest clinical efficacy [88]. These findings highlight two major challenges: drug–drug interactions with AR-targeted therapies and the need for biomarker-guided patient selection, as not all mCRPCs are BCL-2 dependent. Notably, combining venetoclax with CDK4/6 inhibition restored sensitivity to enzalutamide in treatment-resistant PCa with high PRRXX2 expression [89]. Next-generation BH3 mimetics such as navitoclax/ABT-263 [90], sonrotoclax/BGB-11417 [91], lisaftoclax/APG2575 [92], lacutoclax/LP-108 [93] are under clinical evaluation, primarily in hematologic malignancies. In PCa, navitoclax is more effective when combined with Mcl-1 degraders, overcoming resistance in both ADT-naive and CRPC models. Clinical evaluation in CRPC is ongoing, highlighting its therapeutic potential [94]. Future progress will depend on BCL2 dependency profiling, molecular signatures to identify responsive subgroups and development of next-generation BH3-mimetics that avoid toxicities while maintaining potent disruption.

3f. STAT3:STAT3 homodimer

STAT proteins are transcription factors that are activated by tyrosine phosphorylation [95] which leads to SH2 domain-mediated homo- or heterodimerization, and nuclear dimer entry to drive gene transcription (Figure 3A) [96, 97]. Of the 7 STAT family members, STAT3 is most aberrantly expressed in cancer and is constitutively activated in 70% of human cancers [97, 98]. In PCa, phosphorylated STAT3 levels were positively correlated with higher Gleason score and advanced disease stages [99–101], driving mCRPC progression by activating the AR pathway, stem-like phenotypes, epithelial-to-mesenchymal transitions, and tumor-microenvironment interactions [102].

Figure 3. Therapeutic targeting of oncogenic homodimerization in cancer.

Representative oncogenic signaling pathways in which homodimer formation is essential. (A) Upon cytokine or growth factor stimulation, receptor-associated JAK kinases phosphorylate STAT proteins on conserved tyrosine residues. Phosphorylated STATs undergo reciprocal SH2-domain-mediated dimerization, enabling nuclear translocation and transcriptional activation of target genes. Inhibition of STAT dimerization prevents formation of active STAT dimers, thereby suppressing oncogenic transcriptional programs. (B) HSP90 functions as a homodimeric molecular chaperone that undergoes ATP-dependent conformational cycling between open and closed states. This dimeric cycle is required for proper folding and stabilization of multiple oncogenic client proteins. Inhibition of HSP90 homodimerization lead to misfolding and degradation of client proteins critical for tumor growth. (C) Apoptotic pathways rely on dimerization and oligomerization of key signaling components, including caspases and inhibitor of apoptosis proteins (IAPs) such as survivin. Survivin participates in both apoptosis inhibition and mitotic regulation through dimerization and incorporation into higher-order complexes. Disruption of these interactions initiates caspase activation and apoptosis in cancer. (D) Simplified schematic of AR dimerization upon dihydrotestosterone binding, which includes conformational changes that promote N-terminal and C-terminal domain interaction and enable homodimer formation. The AR dimer translocates to the nucleus and activates transcription of AR target genes. Inhibition of the dimer interface prevents AR dimerization despite ligand binding leading to loss of stable complex formation and failure to induce AR target gene expression. The figure was generated using Biorender.

Therapeutic strategies have targeted STAT3 activation both indirectly, by inhibiting upstream kinases [103] and directly, by disrupting SH2-domain mediated dimerization [104]. Since STAT3 can remain active through gain-of-function mutations [105], direct inhibition of STAT3 homodimerization has gained increasing attention [104]. Peptide-based SH2 inhibitors PY*LKTK and [106] S3I-M2001 [107] provided early proof-of-concept that disrupting STAT3 dimerization suppresses cancer growth.. Recently, small molecule SH3 inhibitors, 323–1 and 323–2, directly blocked STAT3 dimerization and IL-6–induced STAT3 Tyr705 phosphorylation in PCa cells with minimal effects on STAT1 signaling [108]. TTI-101 (C-188–9) is the first orally bioavailable small molecule that binds to the STAT3 SH2 phosphopeptide-binding pocket, preventing dimerization and transcriptional activation [109]. It showed effective inhibition of STAT3 signaling, strong anti-tumor activity across multiple cancer models with high intratumoral penetration, [109, 110] and minimal toxicity in phase I and II trials [111]. Although most studies on TTI-101 have focused on non-prostate models, one study showed TTI-101 did not impair mitochondrial respiration or induce STAT3 aggregation in the PCa cell line DU-145 [112], confirming an on-target profile and supporting further investigation. Although clinical evaluation in mCRPC remains limited, preclinical and emerging clinical evidence highlights the therapeutic importance of targeting STAT3 dimerization to counter oncogenic signaling in PCa.

3g. HSP90:HSP90 homodimer

Heat Shock Protein 90 (Hsp90) is a molecular chaperone that is essential for the stability of numerous oncogenic proteins, including AR, HER2, and several kinases that are critical for PCa progression. Hsp90 contains a N-terminal domain (NTD), middle domain, and C-terminal domain (CTD) that drive ATP binding, substrate interaction, and homodimerization, respectively[113]. In its ATP-free state, HSP90 dimers exist in an open, inactive conformation. ATP binding triggers a conformational change to a closed structure that enables HSP90 to clamp around target proteins and promote their proper folding and stabilization [113]. After ATP is hydrolyzed, HSP90 releases the folded client protein and returns to the open conformation, resetting the cycle (Figure 3B) [114]. HSP90 is overexpressed in many cancers, including PCa, where its high expression correlates with poor prognosis[115, 116]. This creates a therapeutic window where inhibiting HSP90 can simultaneously deactivate multiple oncogenic pathways [117].

Most HSP90 inhibitors developed to date target the ATP-binding pocket in its NTD, preventing ATP binding and thus locking it in an inactive state. The majority of these inhibitors fail because of off-target toxicities and the induction of the heat shock response (HSR) that results from activating heat shock factor 1, leading to upregulation of other chaperones like HSP70 and HSP27 as a survival mechanism [116, 118]. An attractive alternative strategy is to inhibit Hsp90’s CTD. Small molecules that bind CTD disrupt the dimer interface and thereby inactivate HSP90 function without competing for the ATP pocket. The classic CTD targeting compound novobiocin, a coumermycin-class antibiotic, does not induce the HSR that N-terminal inhibitors induce [119]. Even though high concentrations of novobiocin were required to achieve anti-cancerous effects, targeting HSP90’s CTD could destabilize oncogenic proteins without triggering HSR. Subsequently, numerous novobiocin analogues with improved potency have been developed that show antiproliferative activity at low concentrations against cancer cells [120–122]. For example, the first-generation novobiocin analogue, F-4 showed enhanced potency in LNCaP and PC-3 PCa cells, reduced cell viability and induced apoptosis while suppressing multiple oncogenic targets. F-4 also decreases PSA levels and does not induce a strong HSR [123]. The second-generation novobiocin-derivatives KU675 and KU-174 also shows potent anti-proliferative effects in ADT-naive and CRPC models and induced target degradation without HSR [116]. Currently, Novobiocin is being tested in a Phase I trial in patients with metastatic or unresectable solid tumors harboring mutations in DNA repair genes (NCT05687110). Continued optimization of CTD-binding inhibitors, along with a deeper understanding of Hsp90 dimerization biology in PCa, may ultimately yield clinically viable therapeutics capable of degrading AR and other critical oncogenic drivers.

3h. Survivin homodimers

Survivin (BIRC5) is a member of the inhibitor of apoptosis proteins (IAP) family which is characterized by a unique baculoviral IAP repeat (BIR) domain [124] and inhibit apoptosis by directly binding to caspases (Figure 3C) [125]. Homodimerization through its N-terminal BIR domain is essential for survivin’s structural stability and its interaction with binding partners [124].

Survivin is not expressed in normal secretory prostate epithelium but highly overexpressed in PCa, particularly in aggressive cancers with high Gleason scores and lymph node involvement [126]. High survivin expression correlates with rapid PSA doubling time, increased proliferation, reduced apoptotic activity [127], and an increased risk of distant metastasis in localized PCa in vitro and in vivo. However, survivin knockdown reduced cell motility by disrupting cytoskeletal organization, polarity, and microtubule dynamics [128]. These findings establish survivin as a critical driver of PCa aggressiveness and progression and provide a compelling rationale to therapeutically target survivin homodimerization.

Crystallographic studies have defined a characteristic “bow-tie” dimer and identified key hydrophobic interface residues that can be pharmacologically targeted [129]. Recently developed small molecule survivin dimerization inhibitors, the LQZ series and its lead compound LQZ-7F, target the critical hydrophobic residues in the survivin dimer interface, disrupting dimerization and inducing spontaneous proteasomal degradation of survivin, resulting in apoptosis, mitotic arrest and inhibition of cancer growth in mouse xenografts models [130]. LQZ-7F was further tested as a pro-drug by hydrolyzing its labile hydrazone linker, releasing the tetracyclic aromatic core, LQZ-7F1. LQZ-7F1 has improved chemical stability, enhanced survivin dimer disruption and degradation and induces apoptosis in PCa cells with synergistic activity when combined with docetaxel [131]. Structure-guided optimization efforts led to a chemically distinct, quinoxaline-based survivin dimerization inhibitor LQZ-7I. LQZ-7I binds the survivin dimer interface through hydrophobic core residues and aromatic amino acids, and disruption of dimerization exposes hydrophobic surfaces that destabilize survivin and triggers its proteasomal degradation rather than transcriptional repression. LQZ-7I induces mitotic defects, caspase activation, and apoptosis in PCa cell lines but exhibited micromolar potency. Its optimized next-generation analogs, 7I10 and 7I14, had improved potency in CRPC cell lines (C4–2 and PC-3). 7I14 suppressed PC-3 xenograft growth while reducing intratumoral survivin levels and inducing apoptosis, without systemic toxicity [132], further validating survivin dimerization as a therapeutically actionable target in advanced PCa.

3i. AR:AR homodimers

AR requires homodimerization for DNA-binding and transcriptional activity. Upon androgen binding, the N-terminal domain (NTD) interacts with the ligand-binding domain (LBD), promoting AR homodimerization, enabling nuclear translocation of dimeric AR and its binding to AREs [133].

Genetic and structural studies showed that disruption of LBD or DNA-binding domain (DBD) mediated dimerization eliminates AR function, underscoring dimerization as a druggable step in AR signaling [134]. AR inhibitors such as enzalutamide target the ligand-binding pocket but do not directly disrupt the dimer interface. Resistance frequently develops through LBD mutations or splice variants such as AR-V7, which lack the LBD yet retain NTD and DBD mediated dimerization and transcriptional activity.

Recent structural studies identified a druggable Dimer Interface Pocket (DIP) at the AR LBD tail-to-tail interface. A first-in-class inhibitor, M17-B15 directly binds this DIP [135], disrupts AR homodimerization and suppresses AR-dependent transcriptional programs in PCa models [136]. Despite suboptimal pharmacokinetics, optimized analogues such as N29 showed improved bioavailability, activity against wild-type and mutant AR and significant growth inhibition in AR-positive PCa xenografts, providing proof-of-concept for DIP targeting [135]. In parallel, small molecule targeting a druggable pocket at the DBT dimer interface, including VPC-17005 and its optimized derivatives (VPC-17160 and VPC-17281) inhibited both full-length AR and AR-V7 without affecting ligand binding, reduced PSA levels, and suppressed PCa growth [137] [138]. Collectively, these findings establish also AR dimerization as a therapeutically actionable target and support further development of dimer interface–targeting agents for advanced CRPC.

4. Clinical and Translational Challenges: future prospectives

While dimer interfaces play a crucial role in key oncogenic and survival pathways, their complex physico-chemical and biological characteristics can pose significant challenges for rational drug design and clinical translation (Table 1). Below, we have outlined the major biological and drug-development hurdles that have hindered the therapeutic targeting of PPIs, while also highlighting emerging strategies to overcome these barriers.

Table 1.

Therapeutic strategies to target protein dimerization

Therapeutic strategies	Mechanism of action	Advantages	Limitations
Small-molecule inhibitors	Directly occupy hot spots at the dimer interface to prevent partner binding	Orally bioavailable; scalable; suitable for intracellular targets	Flat featureless interfaces; modest affinity; resistance to mutations
Small allosteric molecules	Bind distal sites to destabilize dimerization or shift equilibrium toward monomer	Can avoid flat interface, high specificity	Difficult to identify and validate the allosteric sites, context dependent effects
Stapled peptides	Mimic α-helices of one partner to competitively block binding	High specificity; strong binding; rational design	Delivery, stability and bioavailability issues; immunogenicity
Macrocyclic peptides	Constrained interface engagement (rigid structures enhance affinity to extended PPI surfaces)	Improved potency over linear peptides	Manufacturing complexity, poor oral availability
Peptidomimetics	Partial interface mimicry (reproduce key binding residues in smaller chemical scaffolds)	Balance between size, affinity and permeability	Reduced structural fidelity; moderate potency
PROTACs	Induce ubiquitination and proteasomal degradation of one dimer partner	Overcomes high protein abundance; durable effects; bypasses interface	Off-target degradation; resistance
Molecular glues	Stabilize non-productive interactions that prevent native dimerization	High potency at low doses	Limited predictability; difficult to rationally design
Antibodies/nanobodies	Sterically prevent extracellular or receptor dimerization	High specificity; long half-life	Limited to extracellular targets
AI-guided/structure-based design	Rational interface targeting (uses AlphaFold, MD simulations, and PPI hotspot mapping)	Expands druggable space, cost and time efficient	Computational and experimental validation needed

4a. Structural complexity of PPIs

Protein-interacting interfaces are typically large and physically flat, which makes designing small molecules that specifically target these interfaces difficult as they lack deep pockets for small molecules to bind with high specificity and affinity [29, 139, 140]. Additionally, many dimerization surfaces contain disordered or flexible regions and can be dynamic. These proteins often undergo conformational changes or only form transient complexes, complicating pharmacological targeting [29, 140]. Biophysical approaches such as cryo-EM and hydrogen-deuterium exchange mass spectrometry have identified that PPIs often involve regions of ‘soft disorder’, which makes the rational design of inhibitors or disruptors particularly difficult [141, 142]. As example, the PPI interface between Bcl-2 and Bak/Bax is large, flat, and lacks cavities, properties that long rendered Bcl-2 ‘undruggable.’ This perception changed with the advent of alanine-scanning technologies, which identified key binding sites and renewed interest in development of Bcl-2 PPI inhibitors[28]. This example underscores that ‘undruggable’ can reflect current technological limits rather than biological impossibility. As computational power increases and structural predictions become more refined, optimism increases to uncover actionable structural features, especially within disordered regions.

4b. Off-target effects and compensatory signaling

The lack of well-defined cavities exposes another major challenge; specificity. Because PPIs rely on broad, relatively featureless surfaces, an inhibitor designed for one interaction can mistakenly disrupt other physiologically important dimers, leading to off-target effects. For example, the peptidomimetic IIA6B17 was the first small molecule inhibitor designed to block Myc–Max dimerization, but it also inhibited c-Jun because both proteins share a similar leucine-zipper interface. As a result, such Myc-targeted agents mistakeably disrupted AP-1 (Jun-Fos) activity [51, 143]. Similarly, Stattic, a small-molecule designed to inhibit Tyr705-dependent STAT3 dimerization, also inhibits STAT1 and STAT2 dimerization as the STAT proteins share conserved p-Tyr binding pocket[144]. Despite these challenges, other examples show that PPI targeting and achieving specificity is possible. DEL-22379 inhibits ERK dimerization and blocks tumor-cell proliferation without off-target activities [145].

Another problem is pathway compensation, which is not unique to PPI modulators. Cancer signaling pathways are highly redundant and interconnected, allowing cells to bypass blocked protein functions by redirecting signaling through alternative pathways. Thus, disruption of one signaling dimer may trigger compensatory feedback loops, activating parallel pathways that compensate for the function of inhibited protein and drive tumor survival and growth. In HER2-positive breast cancer, pertuzumab blocks the HER2-HER3 heterodimer, but loss of HER2 signaling de-represses estrogen receptor (ER) activity, allowing ER-mediated transcription to compensate [146]. This highlights why multi-targeted approaches should be preferred, targeting multiple nodes of a signaling network and why PPI modulators are attractive as additives to existing therapies or as sequential supplements in multi-blockade strategies.

4c. Tumor heterogeneity and resistance development

Cancers may eventually develop resistance to PPI-modulating drugs. Beyond pathway compensation, one mechanism is mutational escape, where cancer cells acquire mutations at the drug-binding PPI “hot spots,” reducing the drug’s affinity without completely abolishing PPI. Additional mutations may occur at amino acids under post-translational modification (PTM) control. For example, molecular dynamics simulations showed that the dimerization interface of wild-type EGFR is intrinsically disordered and only becomes ordered upon dimer formation. However, cancer-causing EGFR mutations make the dimerization region more structured, allowing EGFR to dimerize more easily and stay active, which drives tumor growth. Phosphorylation at tyrosine residues can also reduce local disorder, potentially leading to autonomous EGFR signaling [147]. These findings highlight the need to design inhibitors that target multiple sites within a PPI interface that provide additional layers of regulation and enhance specificity.

Resistance can also arise from insufficient drug persistence in the tumor. PPI modulators with short half-lives or suboptimal delivery may fail to maintain therapeutic pressure, allowing rebound dimerization and survival of resistant clones. To this end, it is also crucial that drugs effectively inhibit the targeted PPIs at a biosafe level.

4d. Drug Delivery and Stability Challenges

Even once an effective, specific, and biosafe PPI modulator is developed, delivering it to cancer cells at therapeutic concentrations remains a major challenge. Cell permeability is a critical barrier, particularly for large biologics, since many key PPIs in PCa are intracellular. Monoclonal antibodies, due to their large size and hydrophilicity, are largely restricted to extracellular targets and cannot be administered orally. When delivered intravenously or subcutaneously, they often have limited tissue penetration and uneven distribution within solid tumors.

Peptide-based PPI modulators, though smaller, rarely cross cell membranes passively and are highly susceptible to protease degradation, resulting in short systemic half-lives and rapid clearance [148]. This necessitates frequent dosing or specialized formulations. Chemical modifications such as cyclization, hydrocarbon stapling, and cell-penetrating peptide conjugations can enhance stability and uptake, but at the cost of increased development complexity [10, 149]. For example - Omomyc, a peptide-based inhibitor of MYC-MAX dimerization that is retained for at least 72 hours after administration, underwent multiple stabilizing design modifications, including targeted mutations in the leucine zipper that to promoted dimerization [150].

Small-molecule PPI inhibitors have their own pharmacokinetic challenges. Because they must bind to large, relatively flat protein interfaces, they are often larger and more hydrophobic than conventional small-molecule drugs, resulting in poor aqueous solubility and low oral bioavailability. Excessive hydrophobicity can also cause off-target toxicities and complicated formulation [151]. As with biologics and peptides, extensive medicinal chemistry, such as introducing polar substituents or replacing aromatic rings with heterocycles is often required to optimize solubility and exposure [152, 153].

Moreover, systemic delivery can be especially challenging in PCa, where PPI inhibitors must accumulate in the cancer at therapeutic levels. It is even more difficult in metastatic PCa, where bone lesions introduce barriers like poor vasculature, dense mineralized matrix, and unique biochemical microenvironment further hinder drug penetration and distribution [154, 155].

4e. Biomarker-based patient selection

Another major barrier to the clinical translation of dimerization-targeted therapies in PCa is the absence of robust biomarker-driven patient selection strategies. Because dependence on specific dimeric complexes varies across disease states and molecular subtypes, predictive biomarkers will be essential to identify cancers that are biologically dependent on a given interaction. For example, BCL-2 family inhibition may be most effective in tumors with high BCL-2 overexpression or high apoptotic priming [85], while MDM2 inhibitors are likely benefit patients with intact wild-type p53 signaling [67, 68]. Similarly, STAT3-directed approaches may benefit patients with elevated IL6–STAT3 pathway activity [108], and HIF-α:ARNT inhibition may be rational in hypoxia-enriched or highly vascularized cancers [41, 42].

As discussed earlier, the clinical experience with BCL-2 inhibition highlights the importance of biomarker-guided patient selection for dimer-targeted therapies. Venetoclax efficacy was limited by drug–drug interactions with AR inhibitors and the absence of molecular stratification [88]. The success of biomarker-guided treatments in PCa, most notably the use of PARP inhibitors in patients harboring homologous recombination repair (HRR) gene alterations [156], shows the clinical feasibility and impact of molecularly stratified therapy. Developing comparable predictive frameworks for dimerization-targeted agents will therefore be critical to align dimer-targeted therapies with the appropriate molecular subsets of PCa and maximize clinical benefit.

5. Emerging advancements and opportunities

As outlined, each class of PPI inhibitors has its own limitations. Biologics have high specificity but limited cell permeability and tumor penetration. Peptides have tunable structures but poor stability and membrane crossing. Small molecules have better tissue distribution but often suffer from solubility and bioavailability constraints. Despite these hurdles, PPI inhibitors hold a major advantage - they can achieve exceptional target specificity by recognizing unique structural pockets at protein interfaces. Rationally designed macrocycles and stapled peptides can be engineered to precisely match such structural geometries, reducing off-target activity. Recent technological advances now allow to overcome earlier constraints. Improvements in peptide chemistry such as stapling, cyclization, D-amino acids, are boosting metabolic stability, intracellular uptake, and overall bioavailability [157]. For example, a stapled peptide ALRN-6924 targeting MDM2/MDMX has entered phase I/II for solid tumors [158]. A recently designed double-stapled peptide (DSARTC) simultaneously binds the AR DNA-binding domain and the E3 ligase MDM2; this peptide-PROTAC degraded both full-length AR and AR-V7 in enzalutamide-resistant PCass, suppressing in vivo growth [159]. Simultaneous developments in improving drug delivery systems, such as nanoparticle carriers, albumin conjugates, and peptide-nanoparticle hybrids, facilitate large or polar PPI inhibitors to reach tumors more effectively [160]. For instance, in PCa models ultra-small gold nanoparticle-peptide conjugates have effectively delivered DNA-binding domain degraders capable of eliminating AR and AR-V7 [161]. Targeted protein degradation is emerging as another powerful strategy to bypass resistance mechanisms. PROTAC molecules recruit E3 ligases to destroy oncogenic proteins, eliminating both their enzymatic and scaffolding functions [162]. AR-targeting degraders such as ARV-110 and ARV-766 have already reached clinical trials, showing activity against wild-type, mutant, and splice-variant AR (including AR-V7) [163]. Other degraders such as MTX-23 and ARCC-4, can eliminate both AR and variant forms in resistant CRPC models [164, 165]. Artificial intelligence (AI) and machine learning are being used to design and refine PPI inhibitors. Deep-learning platforms like DeepPROTACs can effectively predict PROTAC degradation efficiency based on target and E3 structures [166], enabling rapid optimization. Structure-based modeling with Rosetta has been used to create new macrocyclic peptidomimetics that bind the β-catenin N-terminal hairpin pocket, potently block β-catenin:TCF interaction, downregulate AR, Myc, Cyclin D1 signaling and suppress PCa cells proliferation with nanomolar efficacy [167]. AlphaFold can reveal cryptic hot spots and even de novo generates cyclic peptide inhibitors [168]. RNA-guided and diffusion-based protein design tools such as RFdiffusion based RFpeptides can now design novel cyclic peptides from scratch, opening the door to targets that previously had no existing inhibitors [169]. In sum, the convergence of protein design algorithms, peptide chemistries, and novel degrader modalities can open access to “undruggable” oncogenic interactions in PCa. Finally, the scope of targets that could serve as viable hits for therapeutically preventing dimerization events in PCa is expanding. Proteins that require dimerization to exert their function and that mediate aggressive PCa progression, such as AR and EGFR, have recently been subject to PPI inhibition approaches [19, 135–138].

Conclusion

Our literature review suggests that PPI-targeting therapies, particularly dimerization-dependent complexes, could translate effectively into PCa clinic, but is still an underexploited therapeutic opportunity. As high-resolution structural tools like cryo-EM, computational modeling, AI-driven PPI design, and advanced delivery platforms continue to develop, and as dosing optimization and predictive biomarkers improve, the range of druggable PPIs in PCa could expand rapidly.

Looking forward, direct targeting of oncogenic dimerization complexes offer potential benefits over conventional therapies and overcome acquired treatment resistance (Table 2). Among these, the AR:AR homodimer remains the most prostate-specific target and represents the central driver of CaP growth. While current AR-targeted therapies indirectly disrupt AR function, direct pharmacologic disruption of AR dimerization remains relatively underexplored, highlighting an opportunity for therapeutic intervention. In contrast, several other dimers discussed in this review represent broader oncogenic dependencies that become particularly relevant in advanced and therapy-resistant stages. Importantly, many of these dimeric networks intersect functionally with androgen signaling and contribute to resistance mechanisms. For example, MDM2 inhibition restores p53 activity and enhances sensitivity to ADT and radiation in preclinical models. Targeting the MDM2-p53 interaction along with AR inhibition represents a promising therapeutic strategy in CRPC models that retain wild-type 53. Similarly, BCL-2 family dimers are frequently upregulated in CRPC, and the BH3 mimetics can increase ADT-induced apoptosis. HER2:HER3 signaling has been associated with microenvironment-driven resistance to ADT, while HSP90 inhibition can destabilize multiple oncogenic client proteins, including AR and HER2. Constitutive STAT3 activation promotes tumor survival and inflammatory signaling, and its inhibition induces apoptosis in PCa. MYC:MAX dimers drive aggressive and neuroendocrine phenotypes and although historically considered undruggable, are now emerging as pharmacologically druggable target. Similarly, HIF-α:ARNT dimers support hypoxia-driven castration resistance, and both hypoxia and IL6–STAT3 signaling axes may be upregulated following ADT, suggesting rational opportunities for combinatorial targeting. Survivin homodimers are overexpressed in PCa; however, therapeutic targeting has thus far demonstrated limited efficacy. All these interactions represent context-specific vulnerabilities linked to microenvironment adaptation, lineage plasticity, or hypoxia-driven resistance. Notably, several of these targets were previously considered undruggable, but are now becoming accessible through recent advances in PPI-directed drug design. Also, dimerization-dependent signaling rarely functions in isolation, highlighting the benefits of rational combination strategies.

Table 2.

Targeting protein dimerization versus established PCa therapeutic approaches.

Strategy	Mechanism of Action	Key Advantages	Limitations
Protein-Protein Dimerization Inhibitors	Disrupt formation of functional dimer required for activation of transcription factor, signaling complex, etc.	Applicable to multiple clinically relevant targets, directly blocks functional activation step, enables targeting of non-enzymatic proteins, potential for high specificity, overcomes acquired resistance to established PCa therapeutics	Protein-protein interfaces can be large and flat with limited druggable pockets, resistance mutations at interaction interfaces may emerge, patient selection may be challenging
Androgen Deprivation Therapy (ADT)	Prevents ligand-activation of AR	Directly inhibits the key oncogenic driver in PCa, proven survival benefit, effective in early-stage and metastatic hormone-sensitive disease, well-established standard of care	Significant systemic side effects, acquired resistance leads to inevitable progression to CRPC, induction of NEPC in a subset of patients
Chemotherapy	Disrupts microtubule dynamics and inhibits mitosis	AR-independent mechanism, effective in advanced metastatic disease	Systemic toxicity, limited durability of response
Radioligand Therapy	Delivers targeted radiation to PCa cells	PCa-specific targeting, effective in metastatic CRPC	Limited availability, hematologic toxicity, emerging resistance
Immunotherapy	Activates anti-tumor immune response	Durable responses in a subset of patients; systemic anti-PCa immunity	Biomarker limitations, limited efficacy in most PCas, considerable side effects
PARP Inhibitors	Target homologous recombination repair defects via synthetic lethality	Effective in PCa (patients) with HRR gene mutations; biomarker-guided therapy	Applicable only to molecularly defined subset of patients, hematologic toxicity, resistance through restoration of DNA repair pathways

In summary, although their specificity, druggability and clinical advancements varies, these dimeric PPIs converge on key survival and resistance pathways in CaP. Thus, targeting dimerization offers a translational strategy to expand the current therapeutic model in advanced and resistant disease settings.