A 45-year-old woman with ovarian high-grade serous carcinoma undergoes germline BRCA1 testing. BRCA1 is classified as a tumour suppressor gene that functions in homologous recombination repair. The 'BRCAness' phenotype in tumours with BRCA1/2 dysfunction makes them particularly sensitive to which class of drugs by causing synthetic lethality?
- A Topoisomerase I inhibitors (irinotecan)
- B CDK4/6 inhibitors (palbociclib)
- C PARP inhibitors (olaparib) ✓
- D BCL-2 inhibitors (venetoclax)
Explanation
Cells with BRCA1/2 mutations are deficient in homologous recombination (HR) repair of DNA double-strand breaks and rely on base excision repair (BER) mediated by PARP enzymes for single-strand break repair. When PARP is inhibited by drugs such as olaparib, single-strand breaks are converted to double-strand breaks at replication forks; BRCA-deficient cells cannot repair these by HR, leading to genomic catastrophe and cell death — a synthetic lethal interaction. Normal cells with intact BRCA function survive by using HR as backup. This 'BRCAness' concept is the basis for PARP inhibitor use in BRCA-mutated ovarian, breast, prostate, and pancreatic cancers.
Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.