期刊
MOLECULES
卷 27, 期 8, 页码 -出版社
MDPI
DOI: 10.3390/molecules27082491
关键词
ataxia telangiectasia and RAD3-related protein kinase (ATR); DNA damage response (DDR); inhibitor; synergistic effects; cancer therapy
资金
- National Natural Science Foundation of China [82073686, 81730108, 81973635]
- Scientific Research Foundation for Scholars of Hangzhou Normal University [2019QDL003]
- Ministry of Science and Technology of China (High-end foreign experts program) [G20200217005, G2021017004]
- Hangzhou City 115 plan to introduce overseas intelligence projects [20200215, 20210120]
This article introduces the importance of ataxia telangiectasia and RAD3-related protein kinase (ATR) in maintaining genomic integrity and its application in cancer therapy. The article also mentions the sensitivity of ATR inhibition to specific tumor mutations and reports on the increasing number of synergistic anticancer effects involving ATR inhibition. The review summarizes the current research progress and provides perspectives on future challenges and opportunities.
As one of the key phosphatidylinositol 3-kinase-related kinases (PIKKs) family members, ataxia telangiectasia and RAD3-related protein kinase (ATR) is crucial in maintaining mammalian cell genomic integrity in DNA damage response (DDR) and repair pathways. Dysregulation of ATR has been found across different cancer types. In recent years, the inhibition of ATR has been proven to be effective in cancer therapy in preclinical and clinical studies. Importantly, tumor-specific alterations such as ATM loss and Cyclin E1 (CCNE1) amplification are more sensitive to ATR inhibition and are being exploited in synthetic lethality (SL) strategy. Besides SL, synergistic anticancer effects involving ATRi have been reported in an increasing number in recent years. This review focuses on the recent advances in different forms of synergistic antitumor effects, summarizes the pharmacological benefits and ongoing clinical trials behind the biological mechanism, and provides perspectives for future challenges and opportunities. The hope is to draw awareness to the community that targeting ATR should have great potential in developing effective anticancer medicines.
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