PARP inhibitors (olaparib, niraparib) selectively kill BRCA1/2-deficient cancer cells by a concept termed 'synthetic lethality.' The mechanism is:

• A PARP inhibition prevents NAD+ synthesis, starving rapidly dividing cancer cells
• B PARP inhibitors activate p53, inducing apoptosis specifically in BRCA-mutated cells
• C PARP inhibitors prevent mismatch repair, causing hypermutation only in BRCA-mutated tumors
• D PARP inhibition traps PARP-DNA complexes, blocking replication forks; in BRCA-deficient cells (lacking homologous recombination repair), these stalled forks cause catastrophic double-strand DNA breaks and cell death ✓

Explanation

PARP1 normally repairs single-strand DNA breaks via base excision repair. PARP inhibitors trap the PARP-DNA complex at the site of single-strand breaks (a mechanism beyond simple PARP catalytic inhibition). When cells replicate, these trapped complexes cause replication fork collapse into double-strand DNA breaks (DSBs). Normal cells repair DSBs via homologous recombination (HR) using BRCA1/2. BRCA1/2-deficient cancer cells cannot perform HR, making them entirely dependent on PARP-mediated repair — its inhibition causes accumulation of lethal DSBs specifically in BRCA-mutated cells while sparing normal cells (which retain BRCA function).

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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Written and medically reviewed by the StethoPrep medical team.