Overcoming mTOR resistance mutations with a new-generation mTOR inhibitor

• Published in: Nature (London) 2016-06, Vol.534 (7606), p.272-276
• Main Authors: Rodrik-Outmezguine, Vanessa S., Okaniwa, Masanori, Yao, Zhan, Novotny, Chris J., McWhirter, Claire, Banaji, Arpitha, Won, Helen, Wong, Wai, Berger, Mike, de Stanchina, Elisa, Barratt, Derek G., Cosulich, Sabina, Klinowska, Teresa, Rosen, Neal, Shokat, Kevan M.
• Format: Article
• Language: English
• Subjects: 13/106; 13/95; 631/154; 631/67/1059/2326; Animals; Binding sites; Binding Sites - drug effects; Cancer; Cancer cells; Cell Line, Tumor; Drug dosages; Drug resistance; Drug Resistance - drug effects; Drug Resistance - genetics; Female; Humanities and Social Sciences; Humans; Inhibitors; Kinases; letter; Mice; multidisciplinary; Mutation; Mutation - drug effects; Mutation - genetics; Neoplasms - drug therapy; Neoplasms - enzymology; Neoplasms - genetics; Neoplasms - pathology; Oncology, Experimental; Patients; Phosphorylation; Protein Kinase Inhibitors - classification; Protein Kinase Inhibitors - pharmacology; Protein Structure, Tertiary - genetics; Proteins; Rapamycin; Science; Signal Transduction - drug effects; Subpopulations; TOR Serine-Threonine Kinases - antagonists & inhibitors; TOR Serine-Threonine Kinases - chemistry; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism; Xenograft Model Antitumor Assays
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature17963

Inhibitors of the mTOR kinase are in clinical trials for the treatment of cancer; here, mutations in mTOR that can lead to drug resistance are investigated and the results are used to design a new class of mTOR inhibitors that can overcome this resistance. Bivalent mTOR inhibitors counter tumour resistance Inhibitors of the mTOR kinase are in clinical trials for the treatment of cancer. Here Kevan Shokat and colleagues investigate mutations in mTOR that can lead to drug resistance, and identify pre-existing hyperactive kinase domain mutants in cancer patients unresponsive to mTOR treatment. They design a new class of mTOR inhibitor that can overcome this resistance by binding to two sites on the kinase simultaneously and inhibiting signalling and tumour growth in mice. 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 , 3 , 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.