Overcoming mTOR resistance mutations with a new-generation mTOR inhibitor
Vanessa Rodrik-Outmezguine,Masanori Okaniwa,Zhan Yao,Chris J. Novotny,Claire McWhirter,Arpitha Banaji,Helen Won,Wai Wong,M.F. Berger,Elisa de Stanchina,Derek Barratt,Sabina Cosulich,Teresa Klinowska,Neal Rosen,Kevan M. Shokat,Kevan M. Shokat +15 more
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TLDR
A new class of mTOR inhibitors is reported which overcomes resistance to existing first and second generation inhibitors and exploits the unique juxtaposition of two drug binding pockets to create a bivalent interaction that allows inhibition of these resistant mutants.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.read more
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mTOR Signaling in Growth, Metabolism, and Disease.
TL;DR: Recent advances in understanding of mTOR function, regulation, and importance in mammalian physiology are reviewed and how the mTOR signaling network contributes to human disease is highlighted.
mTOR Signaling in Growth, Metabolism, and Disease
TL;DR: Recent advances in understanding of mTOR function, regulation, and importance in mammalian physiology are reviewed and how the mTOR-signaling network contributes to human disease is highlighted.
Journal ArticleDOI
The PI3K pathway in human disease
David A. Fruman,Honyin Chiu,Benjamin D. Hopkins,Shubha Bagrodia,Lewis C. Cantley,Robert T. Abraham +5 more
TL;DR: A perspective on the roles of class I PI3Ks in the regulation of cellular metabolism and in immune system functions is provided, two topics closely intertwined with cancer biology.
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mTOR at the nexus of nutrition, growth, ageing and disease
Grace Y. Liu,David M. Sabatini +1 more
TL;DR: This Review highlights recent advances in the understanding of the complex regulation of the mTOR pathway and discusses its function in the context of physiology, human disease and pharmacological intervention.
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Progress in tumor-associated macrophage (TAM)-targeted therapeutics
TL;DR: This review aims to introduce readers to various aspects in development and evaluation of TAM-targeted therapeutics in pre-clinical and clinical stages of cancer immunotherapies targeting tumor-associated macrophages.
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