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Targeting the ATM Kinase to Enhance the Efficacy of Radiotherapy and Outcomes for Cancer Patients

Targeting the DNA damage response represents a promising approach to improve the efficacy of radiation therapy. One appealing target for this approach is the serine/threonine kinase ataxia telangiectasia mutated (ATM), which is activated by DNA double strand breaks to orchestrate the cellular response to ionizing radiation. Small-molecule inhibitors targeting ATM have entered clinical trials testing their safety in combination with radiation therapy or in combination with other DNA damaging agents. Here, we review biochemical, genetic, and cellular functional studies of ATM, phenotypes associated with germline and somatic cancer mutations in ATM in humans, and experiments in genetically engineered mouse models that support a rationale for investigating ATM inhibitors as radiosensitizers for cancer therapy. These data identify important synthetic lethal relationships, which suggest that ATM inhibitors may be particularly effective in tumors with defects in other nodes of the DNA damage response. The potential for ATM inhibition to improve immunotherapy responses in preclinical models represents another emerging area of research. We summarize ongoing clinical trials of ATM inhibitors with radiotherapy. We also discuss critical ongoing areas of investigation that include discovery of biomarkers that predict for radiosensitization by ATM inhibitors and identification of effective combinations of ATM inhibitors, radiation therapy, other DNA damage response-directed therapies, and/or immunotherapies.

Related Products

Cat.No. Product Name Information
S1092 KU-55933 KU-55933 is a potent and specific ATM inhibitor with IC50/Ki of 12.9 nM/2.2 nM in cell-free assays, and is highly selective for ATM as compared to DNA-PK, PI3K/PI4K, ATR and mTOR. KU‑55933 (ATM Kinase Inhibitor) inhibits the activation of autophagy‑initiating kinase ULK1 and results in a significant decrease of autophagy.

Related Targets

ATM/ATR ULK Autophagy