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Ref Type Journal Article
PMID (16341243)
Authors Thomas GV, Tran C, Mellinghoff IK, Welsbie DS, Chan E, Fueger B, Czernin J, Sawyers CL
Title Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer.
Journal Nature medicine
Vol 12
Issue 1
Date 2006 Jan
URL
Abstract Text 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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Molecular Profile Treatment Approach
VHL inact mut mTORC1 Inhibitor
VHL negative mTORC1 Inhibitor
VHL S65W mTORC1 Inhibitor
VHL N131fs mTORC1 Inhibitor
VHL V155fs mTORC1 Inhibitor
VHL L184P mTORC1 Inhibitor
VHL P86H mTORC1 Inhibitor
VHL R167Q mTORC1 Inhibitor
VHL S68W mTORC1 Inhibitor
VHL R69C mTORC1 Inhibitor
VHL T202* mTORC1 Inhibitor
VHL Y98N mTORC1 Inhibitor
VHL E52fs mTORC1 Inhibitor
VHL L158S mTORC1 Inhibitor
VHL Y112H mTORC1 Inhibitor
VHL H115R mTORC1 Inhibitor
VHL Q96* mTORC1 Inhibitor
VHL S111N mTORC1 Inhibitor
VHL Y112N mTORC1 Inhibitor
VHL C162W mTORC1 Inhibitor
VHL L158P mTORC1 Inhibitor
VHL R161P mTORC1 Inhibitor
VHL S111R mTORC1 Inhibitor
VHL L188V mTORC1 Inhibitor
VHL D126N mTORC1 Inhibitor
VHL S68fs mTORC1 Inhibitor
VHL F119L mTORC1 Inhibitor
VHL R161G mTORC1 Inhibitor
VHL S65L mTORC1 Inhibitor
VHL C77* mTORC1 Inhibitor
VHL G144fs mTORC1 Inhibitor
VHL R167W mTORC1 Inhibitor
VHL F148fs mTORC1 Inhibitor
VHL G114R mTORC1 Inhibitor
VHL Q132fs mTORC1 Inhibitor
VHL K171G mTORC1 Inhibitor
VHL L116fs mTORC1 Inhibitor
VHL F148Lfs*11 mTORC1 Inhibitor
VHL loss mTORC1 Inhibitor
VHL S183L mTORC1 Inhibitor
VHL W88* mTORC1 Inhibitor
VHL P154L mTORC1 Inhibitor
VHL R82P mTORC1 Inhibitor
VHL W117C mTORC1 Inhibitor
VHL N90I mTORC1 Inhibitor
VHL Y98H mTORC1 Inhibitor
VHL R64P mTORC1 Inhibitor
VHL L158fs mTORC1 Inhibitor
VHL P81S mTORC1 Inhibitor
VHL F136L mTORC1 Inhibitor
VHL L163P mTORC1 Inhibitor
VHL L198* mTORC1 Inhibitor
VHL V62fs mTORC1 Inhibitor
VHL S65* mTORC1 Inhibitor
VHL C162F mTORC1 Inhibitor
VHL S68* mTORC1 Inhibitor
VHL H115Q mTORC1 Inhibitor
VHL E70* mTORC1 Inhibitor
VHL N78S mTORC1 Inhibitor
VHL I206* mTORC1 Inhibitor
VHL Q195* mTORC1 Inhibitor
VHL del mTORC1 Inhibitor
VHL W117R mTORC1 Inhibitor
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References