A 47-year-old woman with high-grade serous ovarian carcinoma harbouring a germline BRCA1 mutation is treated with the PARP inhibitor olaparib and achieves a marked response. The selective killing of BRCA-deficient tumour cells by PARP inhibition illustrates which principle?
- A Synthetic lethality, where two defects in parallel repair pathways are individually tolerable but lethal together ✓
- B Angiogenic switch blockade, preventing new vessel formation in the tumour
- C Oncogene addiction, where tumour survival depends on a single activated pathway
- D Immune checkpoint release through enhanced tumour antigen presentation
Correct answer: A. Synthetic lethality, where two defects in parallel repair pathways are individually tolerable but lethal together
Explanation
PARP1 repairs single-strand breaks by base excision repair. When PARP is inhibited, unrepaired single-strand breaks collapse replication forks into double-strand breaks, which normally require homologous recombination. BRCA1-deficient cells lack that second pathway, so they accumulate lethal double-strand breaks while normal cells survive. Oncogene addiction (option C) applies to targeted therapy such as EGFR or BCR-ABL inhibitors, not to this paired-loss principle.
Reference: Robbins and Cotran Pathologic Basis of Disease, 10th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.