CCS-1477

AR coactivators, CBP/p300, are critical mediators of DNA repair in prostate cancer

Castration-resistant prostate cancer (CRPC) remains an incurable stage of the disease with limited effective treatment options. In this context, the androgen receptor (AR) coactivators CBP and p300, which function as histone acetyltransferases, have been identified as key mediators of DNA damage repair (DDR), presenting a novel avenue for therapeutic targeting in CRPC. Key findings indicate that CBP/p300 expression increases as the disease progresses, correlating with poor prognosis in metastatic cases. Inhibition of the CBP/p300 bromodomain enhances responses to standard-of-care therapies.
Functional studies, combined with CBP/p300 cistrome and transcriptome analyses in CRPC, reveal that these coactivators regulate DDR pathways. Mechanistic investigations further demonstrate that therapeutic inhibition CCS-1477 or genomic knockdown of CBP/p300 reduces homologous recombination (HR) factor expression across in vitro models, in vivo systems, and human prostate cancer (PCa) tumors ex vivo. Additionally, CBP/p300 expression in human prostate tissue correlates positively with HR factor levels. Targeting CBP/p300 disrupts HR-mediated repair processes and influences patient outcomes.
Together, these findings establish CBP/p300 as critical drivers of prostate cancer tumorigenesis and provide a foundation for developing optimized therapeutic strategies for advanced prostate cancer. This approach may include CBP/p300 inhibitors in combination with AR-directed therapies and DDR-targeting treatments.

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