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Abstract
Oncogenic activation of the mTOR signaling pathway occurs frequently in tumor cells and contributes to the devastating features of cancer, including breast cancer. mTOR inhibitors rapalogs are promising anticancer agents in clinical trials; however, rapalogs resistance remains an unresolved clinical challenge. Therefore, understanding the mechanisms by which cells become resistant to rapalogs may guide the development of successful mTOR-targeted cancer therapy. In this study, we found that eEF-2K, which is overexpressed in cancer cells and is required for survival of stressed cells, was involved in the negative-feedback activation of Akt and cytoprotective autophagy induction in breast cancer cells in response to mTOR inhibitors. Therefore, disruption of eEF-2K simultaneously abrogates the two critical resistance signaling pathways, sensitizing breast cancer cells to rapalogs. Importantly, we identified mitoxantrone, an admitted anticancer drug for a wide range of tumors, as a potential inhibitor of eEF-2K via a structure-based virtual screening strategy. We further demonstrated that mitoxantrone binds to eEF-2K and inhibits its activity, and the combination treatment of mitoxantrone and mTOR inhibitor resulted in significant synergistic cytotoxicity in breast cancer. In conclusion, we report that eEF-2K contributes to the activation of resistance signaling pathways of mTOR inhibitor, suggesting a novel strategy to enhance mTOR-targeted cancer therapy through combining mitoxantrone, an eEF-2K inhibitor.
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1 Central South University, Department of Pharmacy, The Second Xiangya Hospital, Changsha, China (GRID:grid.216417.7) (ISNI:0000 0001 0379 7164)
2 Central South University, Xiangya School of Pharmaceutical Sciences, Changsha, China (GRID:grid.216417.7) (ISNI:0000 0001 0379 7164)
3 University of Kentucky, Department of Cancer Biology and Toxicology, Department of Pharmacology, College of Medicine, Markey Cancer Center, Lexington, USA (GRID:grid.266539.d) (ISNI:0000 0004 1936 8438)
4 Chinese Academy of Sciences, Translational Medicine R&D Center, Institute of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Shenzhen, China (GRID:grid.9227.e) (ISNI:0000000119573309)
5 Soochow University, Department of Pharmacology, College of Pharmaceutical Sciences, Suzhou, China (GRID:grid.263761.7) (ISNI:0000 0001 0198 0694)
6 Central South University, Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Changsha, China (GRID:grid.216417.7) (ISNI:0000 0001 0379 7164)
7 Central South University, Department of Pathology, Xiangya Hospital, Changsha, China (GRID:grid.216417.7) (ISNI:0000 0001 0379 7164)
8 Central South University, Cancer Research Institute, School of Basic Medicine, and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Changsha, China (GRID:grid.216417.7) (ISNI:0000 0001 0379 7164)