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Published on: March 11, 2021
ATM inhibitors in cancer radiotherapy: Mechanisms, clinical development, and future directions
Raed M Al-Zoubi1, Khalil Garada2, Reem Al Huneidi3
1Surgical Research Section, Department of Surgery, Hamad Medical Corporation, Doha, Qatar; Department of Biomedical Sciences, QU-Health, College of Health Sciences, Qatar University, Doha, 2713, Qatar; Department of Chemistry, Jordan University of Science and Technology, P.O. Box 3030, Irbid, 22110, Jordan.
Abstract:
Ataxia-telangiectasia mutated (ATM) kinase plays a pivotal role in the cellular response to DNA damage. Under normal conditions, ATM acts as a tumor suppressor by regulating pathways that lead to apoptosis and cell cycle arrest via effectors like p53, p21, CHK1, and CHK2. Paradoxically, in some cancers, ATM promotes tumor cell survival and metastasis, especially when aberrantly activated, linking it to therapy resistance and poor outcomes. Its involvement in both radiotherapy and chemotherapy has made ATM an attractive target for cancer treatment. Inhibitors such as KU-55933, KU-60019, and AZD1390 have shown the potential to sensitize cancer cells to radiotherapy by impairing DNA repair, thereby enhancing treatment efficacy. A key challenge remains the development of ATM inhibitors that can effectively cross the blood-brain barrier for use against brain tumors. Currently, none have gained approval from the FDA or EMA, but six candidates, AZD1390, AZD0156, ZN-B-2262, SYH2051, WSD0628 and M3541 are in clinical trials, often as adjuncts to radiotherapy or in combination with PARP inhibitors. Their safety and effectiveness, however, are still under investigation. This review synthesizes ATM's dual roles and the therapeutic promise of targeting ATM in cancer radiotherapy.
Insights
Ataxia-telangiectasia mutated (ATM) kinase has dual roles in cancer, acting as a tumor suppressor or promoting survival. Targeting ATM with inhibitors may enhance cancer radiotherapy, but challenges remain for brain tumor treatment.
Area of Science:
- Oncology
- Molecular Biology
- Radiotherapy
Background:
- Ataxia-telangiectasia mutated (ATM) kinase is crucial for DNA damage response.
- ATM acts as a tumor suppressor normally but promotes cancer survival and metastasis when aberrantly activated.
- ATM's role in DNA repair makes it a target for cancer therapy, particularly radiotherapy.
Purpose of the Study:
- To review the dual roles of ATM kinase in cancer.
- To explore the therapeutic potential of targeting ATM in cancer radiotherapy.
- To discuss challenges and ongoing clinical trials of ATM inhibitors.
Main Methods:
- Literature review synthesizing current research on ATM kinase.
- Analysis of ATM's involvement in DNA damage response pathways.
- Examination of ATM inhibitors' efficacy and clinical trial status.
Main Results:
- ATM exhibits context-dependent roles, acting as a tumor suppressor or promoting cancer progression.
- ATM inhibitors like KU-55933 and AZD1390 show potential in sensitizing cancer cells to radiotherapy.
- Several ATM inhibitors are in clinical trials, often combined with radiotherapy or PARP inhibitors, but none are FDA/EMA approved.
Conclusions:
- Targeting ATM kinase presents a promising strategy to enhance cancer radiotherapy efficacy.
- Development of ATM inhibitors capable of crossing the blood-brain barrier is critical for treating brain tumors.
- Further clinical investigation is required to establish the safety and effectiveness of ATM inhibitors in cancer treatment.
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