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

George Thomas, Chris Tran, Ingo K. Mellinghoff, Derek S. Welsbie, Emily Chan, Barbara Fueger, Johannes Czernin, Charles L. Sawyers

Research output: Contribution to journalArticle

484 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)122-127
Number of pages6
JournalNature Medicine
Volume12
Issue number1
DOIs
StatePublished - Jan 2006
Externally publishedYes

Fingerprint

Kidney Neoplasms
Sirolimus
Positron emission tomography
Positron-Emission Tomography
Tumors
Pharmacodynamics
5' Untranslated Regions
Protein Biosynthesis
Biomarkers
Tumor Suppressor Genes
Neoplasms
Phosphotransferases
Complementary DNA
Genes
Cells
Messenger RNA
Hypoxia
Growth
temsirolimus

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Thomas, G., Tran, C., Mellinghoff, I. K., Welsbie, D. S., Chan, E., Fueger, B., ... Sawyers, C. L. (2006). Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer. Nature Medicine, 12(1), 122-127. https://doi.org/10.1038/nm1337

Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer. / Thomas, George; Tran, Chris; Mellinghoff, Ingo K.; Welsbie, Derek S.; Chan, Emily; Fueger, Barbara; Czernin, Johannes; Sawyers, Charles L.

In: Nature Medicine, Vol. 12, No. 1, 01.2006, p. 122-127.

Research output: Contribution to journalArticle

Thomas, G, Tran, C, Mellinghoff, IK, Welsbie, DS, Chan, E, Fueger, B, Czernin, J & Sawyers, CL 2006, 'Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer', Nature Medicine, vol. 12, no. 1, pp. 122-127. https://doi.org/10.1038/nm1337
Thomas, George ; Tran, Chris ; Mellinghoff, Ingo K. ; Welsbie, Derek S. ; Chan, Emily ; Fueger, Barbara ; Czernin, Johannes ; Sawyers, Charles L. / Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer. In: Nature Medicine. 2006 ; Vol. 12, No. 1. pp. 122-127.
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