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

Nature Medicine volume 12, pages 122–127 (2006)Cite this article

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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Figure 1: Effects of VHL knockdown on sensitivity to CCI-779.
Figure 2: Regulation of HIF expression by mTOR.
Figure 3: Rescue of CCI-779 growth suppression by HIF-1-α and HIF-2-α prolyl hydroxylase mutants.
Figure 4: MicroPET imaging shows VHL and mTOR-dependent glucose uptake.

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Acknowledgements

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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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, 90095, California, USA

    George V Thomas & Emily Chan

  2. Howard Hughes Medical Institute, David Geffen School of Medicine at UCLA, Los Angeles, 90095, California, USA

    Chris Tran & Charles L Sawyers

  3. Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, 90095, California, USA

    Ingo K Mellinghoff, Derek S Welsbie & Charles L Sawyers

  4. Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, 90095, California, USA

    Ingo K Mellinghoff, Barbara Fueger, Johannes Czernin & Charles L Sawyers

  5. Crump Institute for Molecular Imaging, David Geffen School of Medicine at UCLA, Los Angeles, 90095, California, USA

    Ingo K Mellinghoff

  6. Department of Urology, David Geffen School of Medicine at UCLA, Los Angeles, 90095, California, USA

    Charles L Sawyers

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Corresponding author

Correspondence to Charles L Sawyers.

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Supplementary information

Supplementary Fig. 1

Knockdown of VHL is sufficient to cause HIF-1α protein accumulation. (PDF 685 kb)

Supplementary Fig. 2

Effects of VHL knockdown on angiogenesis. (PDF 1782 kb)

Supplementary Fig. 3

VHL mutant cell lines show enhanced sensitivity to CCI-779. (PDF 654 kb)

Supplementary Fig. 4

mTOR activity is reduced during hypoxia. (PDF 2927 kb)

Supplementary Fig. 5

CCI-779 does not affect HIF-1α protein stability. (PDF 1295 kb)

Supplementary Fig. 6

mTOR regulates translation of HIF-1α and -2α in the setting of VHL loss. (PDF 1212 kb)

Supplementary Methods (PDF 29 kb)

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Thomas, G., Tran, C., Mellinghoff, I. et al. Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer. Nat Med 12, 122–127 (2006). https://doi.org/10.1038/nm1337

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