Synthetic lethality in cancer therapy with PARP inhibitors is best described by which statement?

• A. PARP inhibitors kill cancer cells with BRCA/HRD defects while sparing normal cells.
• B. Synthetic lethality occurs when two gene defects together cause cell death.
• C. BRCA/HRD defects spare cancer cells from PARP inhibitors.
• D. PARP inhibitors cause universal cell death regardless of BRCA status.

Answer: (B)

Synthetic lethality is the idea that two genetic problems together are lethal to a cell. In the PARP inhibitor scenario, one defect is BRCA1/2 or other HRD (defective homologous recombination). The other impact is blocking PARP, which is crucial for repairing single-strand breaks. When PARP is inhibited in BRCA-deficient cells, single-strand breaks accumulate and can collapse replication forks into double-strand breaks. Because HR is defective, the cell cannot repair these breaks effectively, leading to cell death. Normal cells, with intact homologous recombination, can still repair the damage and survive, so the effect is selective for BRCA-deficient cancer cells. The other choices either oversimplify the selectivity, claim BRCA defects spare cells, or assert universal death regardless of BRCA status, none of which capture the two-hit lethality concept.