Priority Research Papers:

Point mutations of the mTOR-RHEB pathway in renal cell carcinoma

Arindam P. Ghosh, Christopher B. Marshall, Tatjana Coric, Eun-hee Shim, Richard Kirkman, Mary E. Ballestas, Mitsuhiko Ikura, Mary-Ann Bjornsti and Sunil Sudarshan _

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Oncotarget. 2015; 6:17895-17910. https://doi.org/10.18632/oncotarget.4963

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Arindam P. Ghosh1, Christopher B. Marshall4, Tatjana Coric2, Eun-hee Shim1, Richard Kirkman1, Mary E. Ballestas3, Mitsuhiko Ikura4, Mary-Ann Bjornsti2 and Sunil Sudarshan1

1 Department of Urology, University of Alabama at Birmingham, Birmingham, Alabama, USA

2 Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, Alabama, USA

3 Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, USA

4 Department of Medical Biophysics, Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada

Correspondence to:

Sunil Sudarshan, email:

Keywords: mTOR, RHEB, rapamycin, renal cancer, mutations

Received: June 08, 2015 Accepted: July 03, 2015 Published: July 22, 2015


Aberrations in the mTOR (mechanistic target of rapamycin) axis are frequently reported in cancer. Using publicly available tumor genome sequencing data, we identified several point mutations in MTOR and its upstream regulator RHEB (Ras homolog enriched in brain) in patients with clear cell renal cell carcinoma (ccRCC), the most common histology of kidney cancer. Interestingly, we found a prominent cluster of hyperactivating mutations in the FAT (FRAP-ATM-TTRAP) domain of mTOR in renal cell carcinoma that led to an increase in both mTORC1 and mTORC2 activities and led to an increased proliferation of cells. Several of the FAT domain mutants demonstrated a decreased binding of DEPTOR (DEP domain containing mTOR-interacting protein), while a subset of these mutations showed altered binding of the negative regulator PRAS40 (proline rich AKT substrate 40). We also identified a recurrent mutation in RHEB in ccRCC patients that leads to an increase in mTORC1 activity. In vitro characterization of this RHEB mutation revealed that this mutant showed considerable resistance to TSC2 (Tuberous Sclerosis 2) GAP (GTPase activating protein) activity, though its interaction with TSC2 remained unaltered. Mutations in the FAT domain of MTOR and in RHEB remained sensitive to rapamycin, though several of these mutations demonstrated residual mTOR kinase activity after treatment with rapamycin at clinically relevant doses. Overall, our data suggests that point mutations in the mTOR pathway may lead to downstream mTOR hyperactivation through multiple different mechanisms to confer a proliferative advantage to a tumor cell.

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