A BRCA1-positive woman with advanced high-grade serous ovarian cancer achieves complete clinical response after 6 cycles of carboplatin/paclitaxel. She is started on maintenance therapy. Which mechanism best explains the synthetic lethality exploited by PARP inhibitors in BRCA-mutated cancers?

• A PARP inhibition prevents base excision repair of single-strand DNA breaks; in BRCA-deficient cells unable to perform homologous recombination, double-strand breaks accumulate, causing cell death ✓
• B PARP inhibitors directly inhibit BRCA2 protein function, blocking replication fork stabilization
• C PARP trapping activates the ATM-CHK2 pathway, overriding G2/M checkpoint and forcing mitotic catastrophe in all ovarian cancer cells
• D PARP inhibition upregulates VEGF, sensitizing cells to simultaneous bevacizumab therapy in all ovarian cancer subtypes

Explanation

Synthetic lethality: PARP1 normally repairs single-strand DNA breaks (SSBs) via base excision repair (BER). When PARP is inhibited, SSBs accumulate and convert to double-strand breaks (DSBs) at replication forks. In cells with normal BRCA1/2 function, DSBs are repaired by homologous recombination (HR). In BRCA-mutant cancer cells with deficient HR, DSBs cannot be repaired, leading to genomic instability and cell death — the synthetic lethal interaction. PARP trapping (binding of PARP to DNA) enhances this effect. Olaparib, niraparib, and rucaparib are approved PARP inhibitors for BRCA-mutated ovarian cancer maintenance.

Reference: Shaw's Textbook of Gynaecology, 17th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.