PARP Inhibitor Resistance Mechanism and Strategies to Overcome Them for More Effective Anti-cancer Treatment

Background: Traditional cancer treatments have increased survival, but their efficacy is frequently constrained by toxicity and drug resistance. Cancer is still a major global health concern. Although resistance, notably to PARP1 inhibitors, has emerged as a significant therapeutic obstacle, PARP inhibitors have demonstrated promise, particularly in BRCA-mutated and HR-deficient malignancies. Objective: Furthermore, highlighting current developments in addressing these treatment obstacles, this review investigates the molecular and cellular mechanisms driving acquired and inherent resistance to PARP inhibitors. Methods: A thorough review of the literature was conducted using specific keywords from Google Scholar, PubMed, and Scopus. To gather relevant information on resistance mechanisms and therapeutic options, 119 peer-reviewed articles were carefully analyzed. Result: Replication fork protection, drug efflux through ABC transporters, homologous recombination restoration, and PARP1 mutations are important resistance mechanisms to PARP inhibitors. Combination treatments, epigenetic modulators, and next-generation PARP inhibitors with enhanced target selectivity are methods for overcoming resistance. Conclusion: For researchers seeking to develop more effective and long-lasting anti-cancer treatments, this review provides a comprehensive framework for understanding PARP inhibitor resistance and exploring new therapeutic approaches.