Ataxia–telangiectasia mutated (ATM) is a central regulator of the DNA damage response (DDR), coordinating DNA double-strand break signaling, checkpoint activation, and maintenance of genome stability. Although traditionally regarded as a tumor suppressor, accumulating evidence indicates that many established cancers become functionally dependent on residual ATM signaling to tolerate oncogene-driven replication stress, genomic instability, oxidative stress, and defective checkpoint control. This context-dependent reliance reflects a form of non-oncogene addiction in which ATM signaling is selectively retained to sustain tumor cell survival, particularly in TP53-deficient and highly replication-stressed malignancies. Beyond canonical DDR functions, ATM also contributes to tumor progression through regulation of NF-κB signaling, epithelial–mesenchymal transition, hypoxia adaptation, metabolic rewiring, mitochondrial homeostasis, and immune modulation. These diverse activities provide a strong rationale for therapeutic ATM inhibition. Pharmacological ATM inhibitors impair checkpoint signaling and DNA repair, thereby sensitizing tumors to radiotherapy and DNA-damaging agents and promoting synthetic lethal interactions in DDR-deficient backgrounds. In this review, we aim to integrate current mechanistic, preclinical, and translational evidence linking ATM biology with the pharmacological and clinical development of small-molecule inhibitors, including KU-55933, KU-59403, KU-60019, CP466722, WSD0628, AZD0156, AZD1390, M3541, SYH2051, and XRD-0394. We further discuss emerging concepts such as context-specific synthetic vulnerabilities, radio-immunotherapy combinations, pharmacokinetic and toxicity considerations, mechanisms of resistance, and the limitations of current preclinical models. Collectively, ATM inhibition represents a promising precision oncology strategy for exploiting DDR dependencies and overcoming therapeutic resistance in genetically unstable cancers.
Kciuk et al. (Thu,) studied this question.