Understanding mechanisms of PARP inhibitor resistance

PARP inhibitors exploit homologous recombination repair (HRR) deficiencies, including BRCA1/2 mutations, but intrinsic and acquired resistance limit durable benefit. We review clinically relevant resistance mechanisms, emphasizing restoration of BRCA function or HRR through reversion mutations, gene re-expression, hypomorphs and DNA repair rewiring. HRR-independent mechanisms, including drug efflux and reduced PARP trapping, are also considered. Understanding these pathways should guide biomarkers, next-generation agents and rational combinations to overcome resistance in patients.