Synthetic Lethality in Cancer: Mechanistic and Therapeutic Insights into PARP Inhibitors, BRCA Mutations, and Homologous Recombination Deficiency (HRD)

Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) represent a paradigm shift in precision oncology, exploiting synthetic lethality to selectively target tumor cells deficient in homologous recombination repair (HRR) pathways, particularly those harboring BRCA1/2 mutations (Lord & Ashworth, 2017). PARP enzymes, primarily PARP1 and PARP2, are central to the repair of single-strand DNA breaks through the base excision repair pathway. Pharmacologic inhibition of PARP leads to persistent DNA damage accumulation, replication fork collapse, and lethal double-strand breaks in HRR-defective cells (Pommier et al., 2016; Ray Chaudhuri & Nussenzweig, 2017).Loss-of-function mutations in BRCA1, BRCA2, or other HRR genes (e.g., ATM, PALB2, RAD51) define a homologous recombination–deficient (HRD) phenotype that confers enhanced susceptibility to PARPi-induced cytotoxicity (Noordermeer & van Attikum, 2019). The clinical efficacy of PARPi—including olaparib, niraparib, rucaparib, and talazoparib—has been validated in multiple phase III trials across ovarian, breast, prostate, and pancreatic cancers, establishing improved progression-free survival in patients with BRCA-mutant or HRD-positive tumors (Moore et al., 2018; de Bono et al., 2020; Golan et al., 2019).Beyond monotherapy, combination regimens integrating PARPi with anti-angiogenic agents (e.g., bevacizumab), immune checkpoint inhibitors, or DNA damage response (DDR) modulators have demonstrated synergistic potential by amplifying DNA damage, modulating tumor immunity, and overcoming resistance mechanisms (Mirza et al., 2016; Zhou et al., 2024). Circulating tumor DNA (ctDNA)–based HRD assays and genomic scar signatures are emerging as minimally invasive biomarkers for monitoring response and detecting resistance evolution (Hoppe et al., 2022).Despite these advances, unresolved questions persist regarding inter-agent comparability, sequencing in overlapping indications, and optimal biomarkers for HRD detection. Resistance mechanisms, including secondary BRCA reversion mutations, replication fork stabilization, and altered PARP trapping, further limit durable efficacy (Lord & Ashworth, 2017; Lin et al., 2023). Future research integrating multi-omic profiling, standardized HRD testing, and adaptive clinical trial designs will be essential to refine patient selection and expand therapeutic benefit beyond BRCA-mutated populations (Zhou et al., 2024; Lin et al., 2023).In conclusion, PARP inhibition embodies a mechanistically grounded and clinically validated strategy for exploiting synthetic lethality in cancer therapy. Continued elucidation of HRD biology, biomarker evolution, and rational drug combinations will underpin next-generation approaches to overcome resistance and enhance long-term outcomes in precision oncology.