Targeting ATM Kinase in Cancer—A Comprehensive Review
6 affiliations
- 1Department of Molecular Biotechnology and Genetics, University of Lodz, Lodz, Poland
- 2Department of Functional Genomics, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
- 3BioMedChem Doctoral School of the University of Lodz and Lodz Institutes of the Polish Academy of Sciences, Lodz, Poland
- 4Department of Inorganic and Analytical Chemistry, University of Lodz, Lodz, Poland
- 5Doctoral School of Exact and Natural Sciences, University of Lodz, Lodz, Poland
- 6Doctoral School of Molecular Medicine, Medical University of Lodz, Lodz, Poland
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.
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BibTeX
@article{kciuk2026targeting,
title = {{Targeting ATM Kinase in Cancer—A Comprehensive Review}},
author = {Mateusz Kciuk and Gabriela Machura and Katarzyna Wanke and Piotr Gromek and Beata Marciniak and Renata Kontek},
journal = {Oncology Research},
year = {2026},
month = oct,
doi = {10.32604/or.2026.082180},
url = {https://doi.org/10.32604/or.2026.082180},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Targeting ATM Kinase in Cancer—A Comprehensive Review
AU - Mateusz Kciuk
AU - Gabriela Machura
AU - Katarzyna Wanke
AU - Piotr Gromek
AU - Beata Marciniak
AU - Renata Kontek
PY - 2026
DA - 2026/10/28
JO - Oncology Research
DO - 10.32604/or.2026.082180
UR - https://doi.org/10.32604/or.2026.082180
AB - 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.
SN - 0965-0407
SN - 1555-3906
ER -