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

Authors: 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.
Article Title: Mechanistically distinct cancer-associated mTOR activation clusters predict sensitivity to rapamycin
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.
Journal Title: Journal of Clinical Investigation
Volume: 126
Issue: 9
ISSN: 0021-9738
Publisher: American Society for Clinical Investigation  
Date Published: 2016-09-01
Start Page: 3526
End Page: 3540
Language: English
DOI: 10.1172/jci86120
PROVIDER: scopus
PMCID: PMC5004947
PUBMED: 27482884
Notes: Article -- Export Date: 3 October 2016 -- Source: Scopus
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MSK Authors
  1. Neal Rosen
    364 Rosen
  2. Yiyu Dong
    16 Dong
  3. James J Hsieh
    114 Hsieh
  4. Emily H Cheng
    55 Cheng
  5. Toshinao Oyama
    6 Oyama
  6. Can Gia Pham
    8 Pham
  7. Zhan Yao
    23 Yao
  8. Jianing Xu
    9 Xu
  9. John Damon Chodera
    54 Chodera
  10. Daniel Lawrence Parton
    9 Parton
  11. Chung-Han   Lee
    38 Lee
  12. Song   Han
    5 Han