Future of PARP inhibitors in cancer treatment: overcoming resistance and enhancing efficacy with combination therapies

Poly(ADP-ribose) polymerase (PARP) is a family of proteins that play a crucial role in diverse cellular processes, including DNA repair, cell death, and changes in chromatin structure. PARP inhibitors (PARPi) have been recognized as notable agents in the realm of anticancer therapeutics owing to their capacity to specifically impact DNA repair pathways, thereby inducing targeted death of cancerous cells, particularly in cancers with homologous recombination deficiency (HRD). These inhibitors have been approved for the treatment of several cancers, such as ovarian, breast, and pancreatic cancers. Despite their promising therapeutic attributes, developing resistance to PARPi presents a formidable obstacle, curtailing their overall efficacy. This article presents a comprehensive description of the potential mechanisms related to PARPi resistance, an in-depth study of potential strategies to overcome resistance, and an assessment of the therapeutic potential of the PARPi in combination with alternative therapies.