A Peptide-Based PROTAC Degrader of BRCA2 Sensitizes Metastatic Castration-Resistant Prostate Cancer to PARP Inhibition

Abstract Defects in homologous recombination repair (HR) make cells highly susceptible to PARP inhibitors. However, the limited efficacy of PARP inhibitors in targeting HR wild-type tumors restricts their broad utility in cancer treatment. Clinical trials of PARP inhibitors have revealed greater efficacy in men with metastatic castration-resistant prostate cancer harboring BRCA2 mutations compared with those with mutations in other HR genes. To address this, we developed a peptide-based proteolysis-targeting chimera (PROTAC) drug that specifically targets BRCA2, leading to its degradation in a DDB1-dependent manner. The interaction between DDB1 and BRCA2 facilitated nuclear accumulation of the BRCA2 peptide PROTAC (BPD), thereby promoting BRCA2 degradation in response to DNA damage. Combining BPD treatment with PARP inhibitors promoted cell death in prostate cancer cells and induced tumor regression in animal models. These findings suggest that the development of a PROTAC drug targeting BRCA2 offers a promising strategy in combination with PARP inhibitor therapy for treating cancers without HR defects. This approach holds potential for expanding the therapeutic application of PARP inhibition for prostate cancer management. Significance: BPD is a peptide-based PROTAC that effectively degrades BRCA2, selectively accumulates in tumor cells, reduces homologous recombination efficiency, and enhances sensitivity to PARP inhibitors in prostate cancer.