Targeting DNA Damage Response Pathways for Cancer Therapy

The DNA damage response (DDR) network comprises interconnected surveillance and repair mechanisms essential for maintaining genomic integrity against endogenous and exogenous threats. Cancer cells frequently harbor DDR pathway defects that paradoxically create therapeutic vulnerabilities exploitable through synthetic lethality principles. Poly (ADP-ribose) polymerase (PARP) inhibitors have revolutionized treatment for breast cancer susceptibility gene (BRCA)-mutated malignancies, validating DDR targeting as a precision oncology approach. Clinical development of ataxia telangiectasia and Rad3-related, ataxia telangiectasia mutated, checkpoint kinase 11/2, DNA-PKcs, and WEE1 inhibitors demonstrates expanding therapeutic applications, with mechanistic synergy when combined with chemotherapy, radiotherapy, and immunotherapy. Biomarker-driven patient selection strategies including homologous recombination deficiency assessment, mutational signature analysis, and replication stress quantification enable the identification of responsive populations beyond germline BRCA mutations. Resistance mechanisms including BRCA reversion mutations, loss of 53BP1/Shieldin complexes, replication fork stabilization, and drug efflux limit the durability of responses, necessitating rational strategies to prevent or overcome therapeutic escape. DDR inhibition enhances anti-tumor immunity through increased mutational burden and cGAS-STING pathway activation, providing a rationale for immunotherapy combinations. Understanding DDR pathway biology, exploiting synthetic lethal interactions, refining biomarker approaches, and developing next-generation inhibitors promise to extend the benefits of DDR-targeted therapy across diverse malignancy contexts while addressing current limitations in therapeutic durability.