Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer.
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.
Thomas
George V
GV
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA.
Tran
Chris
C
Mellinghoff
Ingo K
IK
Welsbie
Derek S
DS
Chan
Emily
E
Fueger
Barbara
B
Czernin
Johannes
J
Sawyers
Charles L
CL
D020121:5' Untranslated Regions; D000818:Animals; D001921:Brain / Q000378:metabolism; D045744:Cell Line, Tumor; D004247:DNA / Q000737:chemistry; D017931:DNA Primers / Q000737:chemistry; D018076:DNA, Complementary / Q000378:metabolism; D003720:Densitometry; D019788:Fluorodeoxyglucose F18 / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D006801:Humans; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism / Q000502:physiology*; D015151:Immunoblotting; D007680:Kidney Neoplasms / Q000378:metabolism*; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D009368:Neoplasm Transplantation; D016133:Polymerase Chain Reaction; D049268:Positron-Emission Tomography; D014176:Protein Biosynthesis; D011494:Protein Kinases / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D019275:Radiopharmaceuticals / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D013997:Time Factors; D014162:Transfection
D020121:5' Untranslated Regions; D017931:DNA Primers; D018076:DNA, Complementary; C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18; D004247:DNA; D008156:Luciferases; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D005947:Glucose