Targeting DNA repair in lung cancer with PARP inhibitors

Lung cancer is a global burden affecting millions of individuals worldwide. Projections indicate a substantial rise in incidence by 2045, with an estimated increase of 131% in males and 105% in females, respectively. Although many therapies are approved for treating lung cancers, the development of acquired resistance to current anti-cancer therapies is a current clinical challenge. This highlights the urgent need for the identification of new biomarkers and the development of novel therapies to further improve treatment outcomes in patients with lung cancer. The emergence of Poly (ADP-ribose) polymerase PARP inhibitors (PARPis) as novel agents in cancer treatment has become a recent focus of research. Although these drugs are approved for other cancer types, such as prostate, ovarian, pancreatic, and breast cancer, they have yet to be approved for use in lung cancer patients. Studies using in vitro, in vivo, and 3D models have shown that PARPis hold promise for targeting lung cancer cells by blocking PARP function in DNA repair pathways. Key challenges associated with the clinical use of PARPis include toxicity and the development of resistance mechanisms. This review aims to critically examine the clinical relevance of PARPis in the context of lung cancer, with a focus on their mechanisms of action, drug interactions, dosing considerations, preclinical and clinical research findings, and the principal limitations hindering their therapeutic efficacy, particularly resistance mechanisms.