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REVIEW

Targeting ATM Kinase in Cancer—A Comprehensive Review

Mateusz Kciuk1,2,*, Gabriela Machura3,4, Katarzyna Wanke1,5, Piotr Gromek2,6, Beata Marciniak1, Renata Kontek1
1 Department of Molecular Biotechnology and Genetics, University of Lodz, Lodz, Poland
2 Department of Functional Genomics, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
3 BioMedChem Doctoral School of the University of Lodz and Lodz Institutes of the Polish Academy of Sciences, Lodz, Poland
4 Department of Inorganic and Analytical Chemistry, University of Lodz, Lodz, Poland
5 Doctoral School of Exact and Natural Sciences, University of Lodz, Lodz, Poland
6 Doctoral School of Molecular Medicine, Medical University of Lodz, Lodz, Poland
* Corresponding Author: Mateusz Kciuk. Email: email

Oncology Research https://doi.org/10.32604/or.2026.082180

Received 12 March 2026; Accepted 27 May 2026; Published online 15 June 2026

Abstract

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.

Keywords

Ataxia-telangiectasia mutated (ATM); ATM kinase; cancer; DNA damage response (DDR); inhibitor

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