Nature Medicine
- 12, 122 - 127 (2005)
Published online: 11 December 2005; | doi:10.1038/nm1337
Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancerGeorge V Thomas1, Chris Tran2, Ingo K Mellinghoff3, 4, 5, Derek S Welsbie3, Emily Chan1, Barbara Fueger4, Johannes Czernin4 & Charles L Sawyers2, 3, 4, 61
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA. 2
Howard Hughes Medical Institute, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA. 3
Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA. 4
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA. 5
Crump Institute for Molecular Imaging, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA. 6
Department of Urology, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA.
Correspondence should be addressed to Charles L Sawyers csawyers@mednet.ucla.edu 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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