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

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

doi:10.1038/nm1337

Cited by 605PI3K/AKT/mTOR signaling in cancerCancer, Hypoxia, and MetabolismRenal cell carcinoma treatment

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

Thomas, George V, Tran, Chris, Mellinghoff, Ingo K, Welsbie, Derek S, Chan, Emily, Fueger, Barbara, Czernin, Johannes, Sawyers, Charles L·2006·Nature Medicine

DOI 10.1038/nm1337

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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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Several studies have shown that mTOR inhibition decreases HIF-1α and HIF-2α levels under both normoxic and hypoxic conditions.
“Consistent with this, several studies have shown that mTOR inhibition decreases HIF-1α and HIF-2α levels under both normoxic and hypoxic conditions (Hudson et al., 2002;Majumder et al., 2004;Thomas et al., 2006;Mohlin et al., 2015).”
From Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer (2016) · cites this paper as Thomas et al., 2006

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“Consistent with this, several studies have shown thatmTOR inhibition decreases HIF-1α and HIF-2α levels under both normoxic and hypoxic conditions (Hudson et al., 2002; Majumder et al., 2004; Thomas et al., 2006; Mohlin et al., 2015).”
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Authors: Thomas, G. V., Tran, C., Mellinghoff, I. K., Welsbie, D. S., Chan, E., Fueger, B., Czernin, J., & Sawyers, C. L.
Affiliations: University of California, Los Angeles (US)
Howard Hughes Medical Institute (US)
Corresponding author: Sawyers, Charles L
ORCID: Thomas, George V
Mellinghoff, Ingo K
Welsbie, Derek S
Chan, Emily
Sawyers, Charles L
Venue: Nature Medicine
Publisher: Springer Science and Business Media LLC
Published: 2005-12-11
Volume: 12
Issue: 1
Pages: 122-127
ISSN: 1078-8956 (ISSN-L)
1546-170X
DOI: 10.1038/nm1337
OpenAlex: W2075997152
Cited by: 604
References: 24
Citations by year: 2026: 1 · 2025: 12 · 2024: 8 · 2023: 7 · 2022: 13 · 2021: 21 · 2020: 17 · 2019: 15 · 2018: 18 · 2017: 21 · 2016: 26 · 2015: 33 · 2014: 39 · 2013: 45 · 2012: 40
FWCI: 16.31
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature Medicine (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Renal cell carcinoma treatment
Keywords: hypoxia-inducible factor-1α, von Hippel-Lindau tumor suppressor, mTOR inhibitors, temsirolimus, kidney cancer, drug sensitivity, protein synthesis inhibition, 5' untranslated region, FDG-PET, pharmacodynamic biomarkers, tumor hypoxia
MeSH terms: Animals, Hypoxia, Brain, Densitometry, DNA, Glucose, Humans, Kidney Neoplasms, Luciferases, Neoplasm Transplantation, Protein Kinases, RNA, Messenger, Time Factors, Transfection, Protein Biosynthesis, Immunoblotting, Polymerase Chain Reaction, DNA Primers, DNA, Complementary, Radiopharmaceuticals, Fluorodeoxyglucose F18, 5' Untranslated Regions, Cell Line, Tumor, Positron-Emission Tomography, Mice, Hypoxia-Inducible Factor 1, alpha Subunit, TOR Serine-Threonine Kinases

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

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