Interplay Between Poly(ADP-ribosyl)ation and Specific Inner Cellular Events That Suggest Combination Strategies for Overcoming PARP Inhibitor Resistance

Therapeutic resistance remains a major obstacle to durable cancer control, with functional reprogramming of the DNA damage response (DDR) network playing a central role. The poly(ADP-ribose) polymerase (PARP) family, particularly PARP1 and PARP2, is crucial for maintaining genomic integrity. By exploiting synthetic lethality, PARP inhibitors (PARPi) selectively target tumors with homologous recombination deficiency (HRD) and are integral to precision therapy in ovarian, breast, and prostate cancers. However, over 40% of patients with BRCA1/2 alterations develop resistance, and patient eligibility remains limited by the low prevalence of HRD mutations. In this review, we summarize the molecular mechanisms of PARPi action, resistance pathways, and emerging combination strategies. PARPi resistance arises through HR restoration (e.g., BRCA1/2 reversion mutations), replication fork protection, RAD51-mediated strand invasion, and metabolic reprogramming. Combination therapies, integrating PARPi with histone deacetylase inhibitors, cyclin-dependent kinase inhibitors, immune checkpoint blockade, or radiation, enhance efficacy by converging on DNA repair pathways and the tumor immune microenvironment. A deeper understanding of coordinated DDR regulation and rationally designed combination regimens will be essential for overcoming PARPi resistance and advancing adaptive, precision-based therapeutic strategies.