DNA damage response in cancer: New treatment strategies

Abstract

Cells have evolved a sophisticated network of biological pathways, collectively termed the DNA damage response (DDR), to coordinate DNA repair, cell cycle checkpoint activation, and other cellular responses, thereby preventing the inheritance of harmful mutations. Genes encoding DDR factors are frequently mutated in cancer, leading to genomic instability and promoting tumorigenesis. However, these mutations also create vulnerabilities that can be exploited for cancer therapy using DNA-damaging cytotoxic drugs and radiotherapy. Advances in our understanding of DDR targeting have illuminated its impact on therapeutic responses, exemplified by tumors with breast cancer suppressor gene 1/2 (BRCA1/2) mutations. Impaired homologous recombination DNA repair in these tumors forces reliance on alternative repair mechanisms, rendering them susceptible to poly ADP-ribose polymerase (PARP) inhibitors. These inhibitors selectively eliminate cancer cells with homologous recombination deficiencies, serving as a paradigm for targeted cancer therapy. Moreover, numerous synthetic lethal relationships between DDR genes have been identified. Consequently, DDR-targeted therapies offer the potential to enhance the efficacy of radiotherapy and chemotherapy in clinical cancer treatment. This review discusses the latest small-molecule DDR inhibitors, with a particular focus on those currently undergoing clinical evaluation.