Understanding DNA and PARP in Cancer: Tackling Inhibitor Resistance

Deoxyribonucleic acid (DNA) is the crucial molecule that stores and transmits genetic information in living organisms. DNA can incur damage from various sources, necessitating efficient DNA repair mechanisms to maintain genomic stability. Cells employ multiple repair pathways, including single-strand repair and double-strand break repair, each involving specific proteins and enzymes. PARPs play a fundamental role in the repair of DNA to detect damage to DNA and facilitate the repair process. PARPi are drugs that inhibit PARP activity, leading to DNA damage accumulation and cell death, particularly in cancer cells with impairments in DNA repair pathways, such as BRCA1/2 mutations. Additionally, PARPi is promising in treating cancer, offering a targeted therapeutic approach. Resistance to PARP inhibitors continues to be an issue in a major clinical challenge. Mechanisms of resistance include homologous recombination repair restoration, increased drug efflux, and mutations in the PARP1 enzyme. Moreover, to overcome this resistance, researchers are investigating combination therapies, targeted therapies that inhibit complementary DNA repair pathways, and novel agents that can counteract resistance mechanisms. Future perspectives focus on enhancing our understanding of resistance mechanisms, developing more effective and selective PARP inhibitors, and identifying predictive biomarkers for therapy response. These advancements aim to improve the efficacy and durability of PARP inhibitor-based treatments, ultimately leading to better outcomes for cancer patients. This review article focuses on the reasons for the evolution of PARP inhibitors, the mechanisms behind resistance, and new strategies to overcome this resistance.