PARP inhibitors (olaparib, niraparib, rucaparib) have transformed the maintenance therapy of advanced ovarian cancer. The mechanism of PARP inhibitor synthetic lethality in BRCA-mutated cells is:

• A PARP inhibitors directly bind and degrade BRCA1/2 proteins in tumour cells
• B PARP inhibition enhances chemotherapy activity by preventing DNA methylation in tumour cells
• C PARP inhibitors activate p53 to induce apoptosis selectively in BRCA-mutated cells
• D PARP inhibition prevents base excision repair, causing persistent single-strand breaks that become irreparable double-strand breaks in cells lacking homologous recombination (BRCA-deficient) ✓

Explanation

The synthetic lethality concept: PARP enzymes are essential for base excision repair (BER) of single-strand DNA breaks (SSBs). PARP inhibition causes accumulation of unrepaired SSBs that stall replication forks and collapse into double-strand breaks (DSBs). Normal cells repair DSBs via homologous recombination (HR). BRCA1/2-mutated cells are HR-deficient and cannot repair these DSBs, leading to cell death (synthetic lethality). PARP inhibitors also 'trap' PARP on damaged DNA, creating cytotoxic PARP-DNA complexes. This mechanism explains selective activity in HR-deficient tumours.

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

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Written and medically reviewed by the StethoPrep medical team.