What is the target of PARP inhibitors and in what tumor context are they most relevant?

• A. PARP inhibitors target tumors with BRCA mutations or homologous recombination deficiency
• B. PARP inhibitors target BRCA wild-type tumors only
• C. PARP inhibitors are used for MMR-deficient tumors
• D. PARP inhibitors cure all cancers

Answer: (A)

The main concept: PARP inhibitors exploit a vulnerability in tumors that have BRCA mutations or other homologous recombination defects. WhenBRCA or HR is defective, cells rely more on PARP-mediated repair of single-strand breaks. Inhibiting PARP leads to unrepaired DNA damage, causing double-strand breaks that the cell can’t fix without HR, which triggers cell death. Normal cells with intact HR aren’t as affected, so the effect is selective for BRCA-mutant or HR-deficient tumors. This makes these inhibitors most relevant in BRCA-mutant cancers or tumors with homologous recombination deficiency, such as some ovarian, breast, prostate, and pancreatic cancers. They’re not limited to BRCA wild-type tumors, aren’t specifically for MMR-deficient cancers, and don’t cure all cancers.