ATM (ataxia telangiectasia mutated) kinase is a central mediator of the DNA damage response (DDR), with established roles in maintaining genomic integrity in response to genotoxic insults. Both germline and somatic alterations in ATM occur frequently in tumors, with pathogenic variants affecting an estimated 1 in 100 individuals worldwide. Emerging evidence has shown its utility as a biomarker for therapeutic sensitivity. ATM-deficient tumors exhibit increased sensitivity to radiotherapy, chemotherapy and present opportunities for synthetic lethality approaches. Notably, ATM loss sensitizes tumors to ATR and PARP inhibitors. This review summarizes the structure and function of ATM kinase and its interacting partners, while addressing critical knowledge gaps in recently described rationale for drug combinations that induce selective synthetic lethality in tumors cells. We examine how these approaches can be leveraged to improve standard chemotherapeutic and immunotherapeutic treatments in cancer. Additionally, we highlight the key preclinical and clinical studies evaluating ATM as a predictive biomarker and discuss its evolving role in precision oncology.
Pham et al. (Wed,) studied this question.