Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer

George V. Thomas; Chris Tran; Ingo K. Mellinghoff; Derek S. Welsbie; Emily Chan; Barbara Fueger; Johannes Czernin; Charles L. Sawyers

doi:10.1038/nm1337

Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer

George V. Thomas
, Chris Tran
, Ingo K. Mellinghoff
, Derek S. Welsbie
, Emily Chan
, Barbara Fueger
, Johannes Czernin
, Charles L. Sawyers

Research output: Contribution to journal › Article › peer-review

580 Scopus citations

Abstract

Inhibitors of the kinase mammalian target of rapamycin (mTOR) have shown sporadic activity in cancer trials, leading to confusion about the appropriate clinical setting for their use. Here we show that loss of the Von Hippel-Lindau tumor suppressor gene (VHL) sensitizes kidney cancer cells to the mTOR inhibitor CCI-779 in vitro and in mouse models. Growth arrest caused by CCI-779 correlates with a block in translation of mRNA encoding hypoxia-inducible factor (HIF1A), and is rescued by expression of a VHL-resistant HIF1A cDNA lacking the 5′ untranslated region. VHL-deficient tumors show increased uptake of the positron emission tomography (PET) tracer fluorodeoxyglucose (FDG) in an mTOR-dependent manner. Our findings provide preclinical rationale for prospective, biomarker-driven clinical studies of mTOR inhibitors in kidney cancer and suggest that FDG-PET scans may have use as a pharmacodynamic marker in this setting.

Original language	English (US)
Pages (from-to)	122-127
Number of pages	6
Journal	Nature medicine
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/nm1337
State	Published - Jan 2006
Externally published	Yes

Funding

This work was supported by grants from the US National Cancer Institute (to G.V.T, I.K.M., C.L.S), the US Department of Defense (to G.V.T., I.K.M., C.L.S.) and Department of Energy (to I.K.M., J.C., C.L.S.). G.V.T. was also supported by grants from the University of California Cancer Research Coordinating Committee, the Stein-Oppenheimer Family Endowment, the Wendy Will Case Foundation and the STOP Cancer Foundation. I.K.M. was also supported by the UCLA Prostate SPORE seed grant. C.L.S. is a Doris Duke Distinguished Clinical Scientist and an Investigator of the Howard Hughes Medical Institute. We thank W.G. Kaelin, G.L. Semenza, J. Gibbons, S. McKnight, R. Bruick, O. Hankinson, A. Dasgupta, R. Strieter, M. Burdick, H. Wu and K. Ellwood-Yen for sharing reagents and advice; members of Sawyers laboratory for helpful discussions and technical assistance; B. Katz for administrative support; M. Costello for graphics support.

Funders
US Department of Defense
US National Cancer Institute
U.S. Department of Energy
Stop Cancer
Wendy Will Case Cancer Fund
University of California-Berkeley, Berkeley California
University of California Los Angeles

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1038/nm1337

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title = "Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer",

abstract = "Inhibitors of the kinase mammalian target of rapamycin (mTOR) have shown sporadic activity in cancer trials, leading to confusion about the appropriate clinical setting for their use. Here we show that loss of the Von Hippel-Lindau tumor suppressor gene (VHL) sensitizes kidney cancer cells to the mTOR inhibitor CCI-779 in vitro and in mouse models. Growth arrest caused by CCI-779 correlates with a block in translation of mRNA encoding hypoxia-inducible factor (HIF1A), and is rescued by expression of a VHL-resistant HIF1A cDNA lacking the 5′ untranslated region. VHL-deficient tumors show increased uptake of the positron emission tomography (PET) tracer fluorodeoxyglucose (FDG) in an mTOR-dependent manner. Our findings provide preclinical rationale for prospective, biomarker-driven clinical studies of mTOR inhibitors in kidney cancer and suggest that FDG-PET scans may have use as a pharmacodynamic marker in this setting.",

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note = "Funding Information: This work was supported by grants from the US National Cancer Institute (to G.V.T, I.K.M., C.L.S), the US Department of Defense (to G.V.T., I.K.M., C.L.S.) and Department of Energy (to I.K.M., J.C., C.L.S.). G.V.T. was also supported by grants from the University of California Cancer Research Coordinating Committee, the Stein-Oppenheimer Family Endowment, the Wendy Will Case Foundation and the STOP Cancer Foundation. I.K.M. was also supported by the UCLA Prostate SPORE seed grant. C.L.S. is a Doris Duke Distinguished Clinical Scientist and an Investigator of the Howard Hughes Medical Institute. We thank W.G. Kaelin, G.L. Semenza, J. Gibbons, S. McKnight, R. Bruick, O. Hankinson, A. Dasgupta, R. Strieter, M. Burdick, H. Wu and K. Ellwood-Yen for sharing reagents and advice; members of Sawyers laboratory for helpful discussions and technical assistance; B. Katz for administrative support; M. Costello for graphics support.",

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AU - Czernin, Johannes

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Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer

Abstract

Funding

ASJC Scopus subject areas

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