PARP inhibitors (olaparib, niraparib) are used as maintenance therapy in ovarian cancer primarily because they exploit which cellular vulnerability in BRCA-mutated tumors?

• A BRCA mutations impair base excision repair; PARP inhibition blocks the only alternative single-strand break repair
• B BRCA-deficient cells cannot perform homologous recombination; PARP inhibition traps the remaining single-strand break repair, causing lethal double-strand breaks (synthetic lethality) ✓
• C PARP overexpression in BRCA tumors makes them selectively sensitive to PARP inhibitors via competitive receptor binding
• D BRCA mutations upregulate PARP expression; PARP inhibitors reduce platinum resistance by blocking PARP-mediated mismatch repair

Explanation

BRCA1/2 proteins are essential for homologous recombination (HR), the high-fidelity repair mechanism for double-strand DNA breaks. PARP enzymes normally repair single-strand breaks (SSBs) via base excision repair. PARP inhibitors trap PARP on DNA at SSBs, converting them to double-strand breaks at replication forks. BRCA-mutated cells cannot repair these by HR, leading to cell death — this is the concept of synthetic lethality. This mechanism forms the basis for olaparib's approval in BRCA-mutated recurrent ovarian cancer and as first-line maintenance after platinum-based chemotherapy.

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

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Written and medically reviewed by the StethoPrep medical team.