期刊
NATURE
卷 534, 期 7606, 页码 272-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nature17963
关键词
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资金
- National Institutes of Health (NIH) [P01 CA094060]
- Breast Cancer Research Foundation
- National Cancer Institute Cancer Center [P30 CA008748]
- Commonwealth Foundation for Cancer Research
- Center for Experimental Therapeutics at Memorial Sloan Kettering Cancer Center
- NIH [P50 AA017072]
- Stand Up 2 Cancer Lung Cancer Dream Team
- Samuel Waxman Cancer Research Foundation
- Howard Hughes Medical Institute
Precision medicines exert selective pressure on tumour cells that leads to the preferential growth of resistant subpopulations, necessitating the development of next-generation therapies to treat the evolving cancer. The PIK3CA-AKT-mTOR pathway is one of the most commonly activated pathways in human cancers(1), which has led to the development of small-molecule inhibitors that target various nodes in the pathway. Among these agents, first-generation mTOR inhibitors (rapalogs) have caused responses in 'N-of-1' cases, and second-generation mTOR kinase inhibitors (TORKi) are currently in clinical trials(2-4). Here we sought to delineate the likely resistance mechanisms to existing mTOR inhibitors in human cell lines, as a guide for next-generation therapies. The mechanism of resistance to the TORKi was unusual in that intrinsic kinase activity of mTOR was increased, rather than a direct active-site mutation interfering with drug binding. Indeed, identical drug-resistant mutations have been also identified in drug-naive patients, suggesting that tumours with activating MTOR mutations will be intrinsically resistant to second-generation mTOR inhibitors. We report the development of a new class of mTOR inhibitors that overcomes resistance to existing first-and second-generation inhibitors. The third-generation mTOR inhibitor exploits the unique juxtaposition of two drug-binding pockets to create a bivalent interaction that allows inhibition of these resistant mutants.
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