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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.
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Research Article Cell biology Oncology Article has an altmetric score of 3

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

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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

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Figure 6

Kidney cancer–derived mTOR-activating mutants are resistant to REDD1-mediated inhibition and can promote rapamycin-sensitive tumor growth in vivo.

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Kidney cancer–derived mTOR-activating mutants are resistant to REDD1-med...
(A) 293T cells, transfected with vectors expressing HA-S6K, the indicated Flag-mTOR mutant, and either GFP or REDD1 were subjected to immunoblot analysis using the indicated antibodies. 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 (t test). (B) Expression of mTOR and shRNA against VHL in NIH/3T3 cells. NIH/3T3 cells stably expressing shRNA against luciferase or VHL (with 2 different constructs) as well as the indicated WT or mutant mTOR (C1483F and S2215F) were serum starved for 1 hour and restimulated with full media for 1 hour before being subjected to immunoblot analysis using the indicated antibodies. (C) NIH/3T3 cells expressing shVHL and the indicated WT or mutant mTOR (C1483F and S2215F) were implanted subcutaneously into the flanks of 6- to 8-week-old female NSG mice. Tumor size was measured for 19 days. Error bars represent SEM. ***P < 0.001 (2 way ANOVA), n = 4. (D) Image of harvested tumors used for C at day 19. (E) NIH/3T3 cells expressing shVHL and mutant mTOR (S2215F) were implanted subcutaneously into the flanks of 6- to 8-week-old male NSG mice. When tumors reached 100 mm3, mice were randomized to received either vehicle or rapamycin treatment 3 times a week for an additional 11 days. Tumor size was measured for 11 days. Error bars represent SEM. **P < 0.01 (2 way ANOVA), n = 4. (F) Image of harvested tumors used for E at day 11 after the start of the treatment.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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