Targeting DNA repair mechanisms in cancer therapy: the role of small molecule DNA repair inhibitors

Abstract

Genomic instability and the accumulation of DNA damage are hallmarks of cancer, often resulting from defects in DNA repair pathways. While normal cells rely on highly coordinated DNA damage response (DDR) mechanisms to maintain genomic integrity, cancer cells exploit aberrant DDR regulation to sustain uncontrolled proliferation and survival. Despite significant advancements in chemotherapy, targeted therapy, and immunotherapy, the emergence of resistance remains a major challenge in cancer treatment. Small molecule inhibitors targeting key DDR proteins have emerged as promising therapeutic agents, not only as direct anticancer drugs but also as indispensable tools for dissecting the molecular intricacies of DNA repair. Recent therapeutic approaches leverage synthetic lethality and DDR pathway vulnerabilities to selectively eradicate tumor cells while minimizing damage to normal tissues. These inhibitors provide insights into mechanisms of tumor resistance, facilitating the rational design of combination therapies to enhance treatment efficacy. This review examines the latest advancements in DNA repair-targeted therapeutics, with a focus on small molecule inhibitors currently under clinical investigation. Additionally, we discuss emerging strategies for optimizing DDR-targeted interventions, including biomarker-driven patient selection and rational drug combinations. Understanding these molecular interactions will contribute to the development of novel, more effective treatment paradigms for cancer therapy. © The Author(s) 2025. Published by Oxford University Press.