Overcoming mTOR resistance mutations with a new-generation mTOR inhibitor Journal Article
| Authors: | Rodrik-Outmezguine, V. S.; Okaniwa, M.; Yao, Z.; Novotny, C. J.; McWhirter, C.; Banaji, A.; Won, H.; Wong, W.; Berger, M.; De Stanchina, E.; Barratt, D. G.; Cosulich, S.; Klinowska, T.; Rosen, N.; Shokat, K. M. |
| Article Title: | Overcoming mTOR resistance mutations with a new-generation mTOR inhibitor |
| Abstract: | 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, 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. 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. © 2016 Macmillan Publishers Limited. All rights reserved. |
| Journal Title: | Nature |
| Volume: | 534 |
| Issue: | 7606 |
| ISSN: | 0028-0836 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2016-06-09 |
| Start Page: | 272 |
| End Page: | 276 |
| Language: | English |
| DOI: | 10.1038/nature17963 |
| PROVIDER: | scopus |
| PMCID: | PMC4902179 |
| PUBMED: | 27279227 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 July 2016 -- Source: Scopus |
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