AR splice variant 7

Functional assays confirm that both LDHA and SRSF2 are critical for CRPC cell proliferation, migration, and tumor growth, and their high expression correlates with poor patient prognosis. Our work establishes a direct mechanistic link between glycolysis and oncogenic splicing via protein lactylation, nominating the LDHA/SRSF2/AR-V7 axis as a therapeutic target.

Unbiased combinatorial screening reveals co-inhibition of nuclear export and translation initiation as a vulnerability in metastatic castration-resistant prostate cancer. Dual targeting of XPO1 and EIF4A1 drives synergistic collapse of oncogenic protein networks, including AR/AR-V7 signaling, to overcome key resistance mechanisms and induce potent antitumor responses across heterogeneous models. Notably, these effects are achieved at substantially reduced doses using clinically tractable agents, defining a mechanistically grounded therapeutic strategy poised for rapid clinical translation.

Collectively, by co-targeting oncogenic drivers and TME vulnerabilities, C19-9N heralds a transformative therapeutic paradigm with profound clinical potential for aggressive PCa.

Collectively, these findings suggest that DNA-PK stimulates the AR and ARv7 activity through its enzymatic function and by stabilizing (or reinforcing) coactivator interactions, including those involving CAND1. In sum, this work advances our understanding of AR isoform actions and identifies additional potential therapeutic targets for castration-resistant prostate cancer.

This work provides direct mechanistic evidence linking an HDAC to RNA splicing, identifies a reversible lipid modification on SF3B2, and expands current understanding of post-translational regulation of spliceosomal proteins and HDAC11 de-fatty acylation substrates. HDAC11 de-fatty-acylates SF3B2 at K10, revealing a previously unrecognized modification on SF3B2.SF3B2 de-fatty acylation enhances alternative splice-site binding in liver cancer cells.HDAC11 regulates RNA splicing through enzymatic de-fatty acylation of a spliceosomal protein.

Emerging therapeutic strategies include proteolysis-targeting chimaeras, N-terminal domain inhibitors, and agents targeting CDK9 or PRMT1. Overcoming AR-V7-mediated resistance will require deeper biological dissection using single-cell multi-omics and the development of rational combination therapies, representing a pivotal challenge in precision oncology for castration-resistant prostate cancer.

KIF15 functions as a context-dependent regulator of mitotic adaptation and tumor progression, with reported roles in mitogenic signaling, metabolic reprogramming, and therapeutic resistance across multiple cancer types. Its chemical tractability and non-redundant role in drug-resistant spindle maintenance position it as a compelling candidate for combination anticancer strategies.

AminoTriComplex was associated with consistent biomarker modulation and occasional exceptional responses; these hypothesis-generating observations warrant validation in larger controlled trials.

91 exhibited favorable pharmacokinetic properties (F = 41%) and significant tumor growth inhibition in CRPC orthotopic models, achieving 66% TGI. This study characterized a distinct subpocket of CDK9 and validated 91 as a promising candidate, paving the way for developing CDK9-targeted therapies to overcome AR dependency in CRPC.

In vivo, ARTADIs outperformed enzalutamide against prostate cancer xenografts in the presence of androgens, underscoring the therapeutic potential of targeting alternative AR domains. These findings support the feasibility - but also highlight the complexity - of developing drugs against an intrinsically disordered TAD impacted by multivalent binding interactions that may not occur in a stepwise fashion.

Maintained B7-H3 expression in various PC settings supports its viability as a target. Associations with AR-related molecular factors, surface antigens, and investigative targets for cell therapy or antibody-drug conjugates (ADC) suggest potential dual-targeting strategies.

Notably, WCF-598 also exhibited a secondary activity by degrading androgen receptor splice variant 7 (AR-V7), a clinically relevant driver of therapy resistance in CRPC. These results establish WCF-598 as a specific chemical probe for investigating the function of RXRγ in CRPC and potentially other RXRγ-related diseases.