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A Peptide-Based PROTAC Degrader of BRCA2 Sensitizes Metastatic Castration-Resistant Prostate Cancer to PARP
1Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
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.
Insights
A novel peptide-drug conjugate targets and degrades BRCA2, enhancing PARP inhibitor efficacy. This strategy shows promise for treating prostate cancers lacking homologous recombination repair defects.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Homologous recombination repair (HR) defects sensitize cells to PARP inhibitors, but efficacy is limited in HR-proficient tumors.
- PARP inhibitors show greater efficacy in metastatic castration-resistant prostate cancer (mCRPC) with BRCA2 mutations than other HR gene mutations.
- Targeting HR wild-type tumors remains a challenge in cancer therapy.
Purpose of the Study:
- To develop a novel therapeutic strategy to overcome resistance to PARP inhibitors in prostate cancer.
- To investigate the potential of targeting BRCA2 degradation using a proteolysis-targeting chimera (PROTAC) approach.
- To evaluate the combination therapy of a BRCA2-targeting PROTAC and PARP inhibitors for mCRPC treatment.
Main Methods:
- Development of a peptide-based PROTAC (BPD) designed to specifically target and induce degradation of BRCA2.
- Investigation of the DDB1-dependent mechanism of BRCA2 degradation mediated by BPD.
- Assessment of the efficacy of BPD in combination with PARP inhibitors in prostate cancer cell lines and animal models.
Main Results:
- The developed BPD effectively induced DDB1-dependent degradation of BRCA2 in prostate cancer cells.
- Combined treatment with BPD and PARP inhibitors resulted in significant cancer cell death.
- Tumor regression was observed in animal models treated with the combination therapy.
Conclusions:
- Targeting BRCA2 degradation with a PROTAC offers a promising strategy to enhance PARP inhibitor therapy for HR-proficient cancers.
- This approach may expand the therapeutic utility of PARP inhibitors in prostate cancer management.
- The BPD-PARP inhibitor combination demonstrates potential for treating mCRPC, particularly in BRCA2-mutated or wild-type tumors.
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