Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer (original) (raw)

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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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

Authors

  1. George V Thomas
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  2. Chris Tran
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  3. Ingo K Mellinghoff
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  4. Derek S Welsbie
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  5. Emily Chan
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  6. Barbara Fueger
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  7. Johannes Czernin
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  8. Charles L Sawyers
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Correspondence toCharles L Sawyers.

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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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