Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
  • Current Issue
  • Past Issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • 100th Anniversary of Insulin's Discovery (Jan 2021)
    • Hypoxia-inducible factors in disease pathophysiology and therapeutics (Oct 2020)
    • Latency in Infectious Disease (Jul 2020)
    • Immunotherapy in Hematological Cancers (Apr 2020)
    • Big Data's Future in Medicine (Feb 2020)
    • Mechanisms Underlying the Metabolic Syndrome (Oct 2019)
    • Reparative Immunology (Jul 2019)
    • View all review series ...
  • Viewpoint
  • Collections
    • Recently published
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • Recently published
  • In-Press Preview
  • Commentaries
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
Mechanistically distinct cancer-associated mTOR activation clusters predict sensitivity to rapamycin
Jianing Xu, … , Emily H. Cheng, James J. Hsieh
Jianing Xu, … , Emily H. Cheng, James J. Hsieh
Published August 2, 2016
Citation Information: J Clin Invest. 2016;126(9):3526-3540. https://doi.org/10.1172/JCI86120.
View: Text | PDF
Research Article Cell biology Oncology

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

  • Text
  • PDF
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 (RAPTOR-mediated) 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 (RHEB-independent) 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.

Authors

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

×

Figure 8

Characterization of the dependency of mTOR double mutants on RAG and RHEB.

Options: View larger image (or click on image) Download as PowerPoint
Characterization of the dependency of mTOR double mutants on RAG and RHE...
(A) 293T cells were transfected with vectors expressing HA-S6K, the indicated Flag-mTOR mutants, and either RAGB plus RAGD (RAGB/DWT) or dominant negative RAGBGDP plus RAGDGTP (RAGB/DMut). Whole cell lysates were analyzed by the indicated immunoblots. (B) HeLa cells stably expressing shRNA against GFP or RHEB were transfected with vectors expressing HA-S6K and the indicated Flag-mTOR mutants and analyzed by the indicated immunoblots. (C) 293T cells were transfected with vectors expressing HA-S6K, the indicated Flag-mTOR mutants, and either GFP or PRAS40 and analyzed by the indicated immunoblots. For A–C, densitometry of phosphorylated S6K versus HA-S6K from 3 independent experiments is shown (mean ± SEM, n = 3 independent experiments). *P < 0.05; **P < 0.01; ***P < 0.001 (t test).
Follow JCI:
Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts