Mechanistically distinct cancer-associated mTOR activation clusters predict sensitivity to rapamycin

Jianing Xu, Can G. Pham, Steven K. Albanese, Yiyu Dong, Toshinao Oyama, Chung Han Lee, Vanessa Rodrik-Outmezguine, Zhan Yao, Song Han, David Chen, Daniel L. Parton, John D. Chodera, Neal Rosen, Emily H. Cheng, James J. Hsieh

Research output: Contribution to journalArticle

49 Scopus citations

Abstract

Genomic studies have linked mTORC1 pathway-activating mutations with exceptional response to treatment with allosteric inhibitors of mTORC1 called rapalogs. Rapalogs are approved for selected cancer types, including kidney and breast cancers. Here, we used sequencing data from 22 human kidney cancer cases to identify the activating mechanisms conferred by mTOR mutations observed in human cancers and advance precision therapeutics. mTOR mutations that clustered in focal adhesion kinase targeting domain (FAT) and kinase domains enhanced mTORC1 kinase activity, decreased nutrient reliance, and increased cell size. We identified 3 distinct mechanisms of hyperactivation, including reduced binding to DEP domain- containing MTOR-interacting protein (DEPTOR), resistance to regulatory associated protein of mTOR-mediated (RAPTORmediated) suppression, and altered kinase kinetics. Of the 28 mTOR double mutants, activating mutations could be divided into 6 complementation groups, resulting in synergistic Rag- and Ras homolog enriched in brain-independent (RHEBindependent) mTORC1 activation. mTOR mutants were resistant to DNA damage-inducible transcript 1-mediated (REDD1- mediated) inhibition, confirming that activating mutations can bypass the negative feedback pathway formed between HIF1 and mTORC1 in the absence of von Hippel-Lindau (VHL) tumor suppressor expression. Moreover, VHL-deficient cells that expressed activating mTOR mutants grew tumors that were sensitive to rapamycin treatment. These data may explain the high incidence of mTOR mutations observed in clear cell kidney cancer, where VHL loss and HIF activation is pathognomonic. Our study provides mechanistic and therapeutic insights concerning mTOR mutations in human diseases.

Original languageEnglish
Pages (from-to)3526-3540
Number of pages15
JournalJournal of Clinical Investigation
Volume126
Issue number9
DOIs
StatePublished - Sep 1 2016
Externally publishedYes

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    Xu, J., Pham, C. G., Albanese, S. K., Dong, Y., Oyama, T., Lee, C. H., Rodrik-Outmezguine, V., Yao, Z., Han, S., Chen, D., Parton, D. L., Chodera, J. D., Rosen, N., Cheng, E. H., & Hsieh, J. J. (2016). Mechanistically distinct cancer-associated mTOR activation clusters predict sensitivity to rapamycin. Journal of Clinical Investigation, 126(9), 3526-3540. https://doi.org/10.1172/JCI86120