Point mutations of the mTOR-RHEB pathway in renal cell carcinoma
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 cel...
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Published in | Oncotarget Vol. 6; no. 20; pp. 17895 - 17910 |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
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20.07.2015
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Abstract | 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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AbstractList | 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. 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. |
Author | Marshall, Christopher B Coric, Tatjana Kirkman, Richard Shim, Eun-Hee Ikura, Mitsuhiko Sudarshan, Sunil Ghosh, Arindam P Ballestas, Mary E Bjornsti, Mary-Ann |
AuthorAffiliation | 3 Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, USA 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 4 Department of Medical Biophysics, Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada |
AuthorAffiliation_xml | – name: 1 Department of Urology, University of Alabama at Birmingham, Birmingham, Alabama, USA – name: 2 Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, Alabama, USA – name: 3 Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, USA – name: 4 Department of Medical Biophysics, Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada |
Author_xml | – sequence: 1 givenname: Arindam P surname: Ghosh fullname: Ghosh, Arindam P organization: Department of Urology, University of Alabama at Birmingham, Birmingham, Alabama, USA – sequence: 2 givenname: Christopher B surname: Marshall fullname: Marshall, Christopher B organization: Department of Medical Biophysics, Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada – sequence: 3 givenname: Tatjana surname: Coric fullname: Coric, Tatjana organization: Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, Alabama, USA – sequence: 4 givenname: Eun-Hee surname: Shim fullname: Shim, Eun-Hee organization: Department of Urology, University of Alabama at Birmingham, Birmingham, Alabama, USA – sequence: 5 givenname: Richard surname: Kirkman fullname: Kirkman, Richard organization: Department of Urology, University of Alabama at Birmingham, Birmingham, Alabama, USA – sequence: 6 givenname: Mary E surname: Ballestas fullname: Ballestas, Mary E organization: Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, USA – sequence: 7 givenname: Mitsuhiko surname: Ikura fullname: Ikura, Mitsuhiko organization: Department of Medical Biophysics, Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada – sequence: 8 givenname: Mary-Ann surname: Bjornsti fullname: Bjornsti, Mary-Ann organization: Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, Alabama, USA – sequence: 9 givenname: Sunil surname: Sudarshan fullname: Sudarshan, Sunil organization: Department of Urology, University of Alabama at Birmingham, Birmingham, Alabama, USA |
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Keywords | mTOR renal cancer mutations RHEB rapamycin |
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SubjectTerms | Adaptor Proteins, Signal Transducing - genetics Adaptor Proteins, Signal Transducing - metabolism Biomarkers, Tumor - genetics Biomarkers, Tumor - metabolism Carcinoma, Renal Cell - drug therapy Carcinoma, Renal Cell - genetics Carcinoma, Renal Cell - metabolism Carcinoma, Renal Cell - pathology Cell Proliferation - drug effects Databases, Genetic DNA Mutational Analysis Drug Resistance, Neoplasm - genetics Genetic Predisposition to Disease GTPase-Activating Proteins - genetics GTPase-Activating Proteins - metabolism HEK293 Cells Humans Intracellular Signaling Peptides and Proteins - genetics Intracellular Signaling Peptides and Proteins - metabolism Kidney Neoplasms - drug therapy Kidney Neoplasms - genetics Kidney Neoplasms - metabolism Kidney Neoplasms - pathology Mechanistic Target of Rapamycin Complex 1 Mechanistic Target of Rapamycin Complex 2 Monomeric GTP-Binding Proteins - genetics Multiprotein Complexes - genetics Multiprotein Complexes - metabolism Neuropeptides - genetics Phenotype Point Mutation Priority Research Paper Protein Kinase Inhibitors - pharmacology Protein Structure, Tertiary Ras Homolog Enriched in Brain Protein Signal Transduction - drug effects Sirolimus - pharmacology TOR Serine-Threonine Kinases - antagonists & inhibitors TOR Serine-Threonine Kinases - genetics TOR Serine-Threonine Kinases - metabolism Transfection Tumor Suppressor Proteins - genetics Tumor Suppressor Proteins - metabolism |
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Title | Point mutations of the mTOR-RHEB pathway in renal cell carcinoma |
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