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Nature. 2016 Jun 9;534(7606):272-6. doi: 10.1038/nature17963. Epub 2016 May 18.

Overcoming mTOR resistance mutations with a new-generation mTOR inhibitor.

Author information

1
Program in Molecular Pharmacology, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
2
Howard Hughes Medical Institute and Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, California 94158, USA.
3
AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK.
4
Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
5
Anti-Tumor Assessment Core, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
6
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
7
Department of Chemistry, University of California Berkeley, Berkeley, California 94720, USA.

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.

PMID:
27279227
PMCID:
PMC4902179
DOI:
10.1038/nature17963
[Indexed for MEDLINE]
Free PMC Article

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