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Ataxia telangiectasia mutated (ATM) kinase as a predictive biomarker in clinical oncology: implications for a
Ann T Pham1, Fenghua Yuan1, Nagaraj S Nagathihalli2
1Division of Colon & Rectal Surgery, Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida; Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida.
Abstract:
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.
Insights
Ataxia telangiectasia mutated (ATM) kinase is crucial for DNA repair. ATM deficiency in tumors increases sensitivity to certain therapies, offering new precision oncology strategies.
Area of Science:
- Molecular Biology
- Genetics
- Oncology
Background:
- ATM kinase is a key regulator of the DNA damage response (DDR), essential for maintaining genomic stability.
- Alterations in ATM are common in various cancers, impacting an estimated 1% of the global population.
- ATM status is emerging as a predictive biomarker for therapeutic response.
Purpose of the Study:
- To review the structure, function, and interactions of ATM kinase.
- To explore the rationale and potential of synthetic lethality strategies targeting ATM-deficient tumors.
- To discuss the role of ATM in enhancing current cancer treatments and its application in precision oncology.
Main Methods:
- Literature review of ATM kinase function, DDR pathways, and synthetic lethality.
- Analysis of preclinical and clinical studies investigating ATM as a biomarker.
- Synthesis of information on ATM-targeted drug combinations and their therapeutic implications.
Main Results:
- ATM-deficient tumors show heightened sensitivity to radiotherapy, chemotherapy, and inhibitors of ATR and PARP.
- Synthetic lethality approaches targeting ATM loss present novel therapeutic opportunities.
- ATM serves as a predictive biomarker for treatment sensitivity in various cancers.
Conclusions:
- Understanding ATM's role is critical for developing targeted cancer therapies.
- ATM-targeted strategies, including synthetic lethality, can improve outcomes in precision oncology.
- ATM evaluation is pivotal for optimizing chemotherapeutic and immunotherapeutic regimens.
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