Elucidating acquired PARP inhibitor resistance in advanced prostate cancer

Area of Science:

• Oncology
• Genetics
• Molecular Biology

Background:

• PARP inhibition (PARPi) demonstrates efficacy in castration-resistant prostate cancer (CRPC) with homologous recombination repair (HRR) defects.
• Mechanisms of PARPi resistance, especially in BRCA2 homozygously deleted (HomDel) CRPC, require further elucidation.
• Acquired mutations restoring BRCA gene function are known resistance mechanisms, but their clinical relevance and generation are unclear.

Purpose of the Study:

• To investigate the mechanisms of PARPi resistance in CRPC, focusing on reversion mutations and their clinical impact.
• To analyze resistance emergence in BRCA2 HomDel CRPC patients treated with PARPi.
• To evaluate the association between reversion events and patient survival outcomes.

Main Methods:

• Analysis of patient samples from the TOPARP-B trial for metastatic CRPC.
• Identification and characterization of reversion mutations in BRCA2/PALB2-mutated tumors.
• Utilizing single circulating-tumor-cell genomics, FISH, and RNAish to study BRCA2 HomDel CRPC resistance.

Main Results:

• Reversion mutations were identified in 79% of BRCA2/PALB2-mutated tumors by treatment end.
• Sixty percent of frameshift deletion reversions were flanked by microhomologies, suggesting POLQ-mediated repair.
• The frequency and timing of reversions correlated significantly with progression-free and overall survival (p < 0.01).
• In BRCA2 HomDel CRPC, selection of rare subclones lacking BRCA2 HomDel was observed under PARPi treatment.

Conclusions:

• Restoration of HRR function through reversion mutations is a key mechanism of PARPi resistance in CRPC.
• POLQ-mediated repair plays a role in generating resistance mutations.
• Understanding these resistance mechanisms is crucial for developing strategies to overcome PARPi resistance in prostate cancer.