Acute BRCAness Induction and AR Signaling Blockage through CDK12/7/9 Degradation Enhances PARP Inhibitor Sensitivity in Prostate Cancer

Current treatment strategies for advanced prostate cancer (PCa) primarily rely on androgen receptor (AR)-directed therapies. However, the emergence of castration-resistant prostate cancer (CRPC) and resistance to AR signaling inhibitors (ARSI) pose substantial challenges. This study introduces a triple degrader, BSJ-5-63, targeting CDK12, CDK7, and CDK9, which has the potential to transform CRPC therapy. BSJ-5-63 uniquely downregulates homologous recombination repair (HRR) genes, including BRCA1 and BRCA2, by degrading CDK12, and it also attenuates AR signaling by degrading CDK7 and CDK9, further enhancing BSJ-5-63's therapeutic impact. Importantly, BSJ-5-63 induces a 'BRCAness' state that persists for a significant duration, enabling rational combination therapy with PARP inhibitors (PARPis) while minimizing drug-related toxicity and resistance. In both in vitro and in vivo studies, potent anti-proliferative effects were observed in both AR-positive and -negative CRPC cells. This research presents a promising multi-pronged approach for CRPC treatment, addressing both DNA repair mechanisms and AR signaling, with the potential to benefit a wide range of patients, regardless of their BRCA1/2 mutational status.