Targeting DNA damage response pathways in tumor drug resistance: Mechanisms, clinical implications, and future directions

Targeting DNA damage response (DDR) pathways has become a promising strategy for overcoming tumor drug resistance, particularly in cancers with DNA repair defects. DDR pathways, including homologous recombination (HR), non-homologous end joining (NHEJ), base excision repair (BER), and mismatch repair (MMR), are essential for maintaining genomic stability. However, resistance to DDR-targeted therapies, such as PARP inhibitors, often arises due to tumor adaptation through various mechanisms. These include HR pathway restoration, mutations in DDR proteins, altered drug metabolism, and the activation of compensatory repair pathways. This review provides a comprehensive analysis of the molecular mechanisms underlying DDR resistance in tumors and explores the clinical implications of these mechanisms in the context of ongoing therapeutic strategies. We also discuss emerging approaches to overcome DDR resistance, including the development of novel DDR inhibitors, combination therapies, and precision medicine approaches based on biomarkers. Furthermore, we highlight future research directions, focusing on the use of advanced technologies, such as CRISPR screening, single-cell sequencing, and artificial intelligence, to uncover new targets and therapeutic strategies to combat DDR-related drug resistance.