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A HIF-regulated VHL-PTP1B-Src signaling axis identifies a therapeutic target in renal cell carcinoma

Suwaki, Natsuko and Vanhecke, Elsa and Atkins, Katelyn M. and Graf, Manuela and Swabey, Katherine and Huang, Paul and Schraml, Peter and Moch, Holger and Cassidy, Amy Mulick and Brewer, Daniel and Al-Lazikani, Bissan and Workman, Paul and De-Bono, Johann and Kaye, Stan B. and Larkin, James and Gore, Martin E. and Sawyers, Charles L. and Nelson, Peter and Beer, Tomasz M. and Geng, Hao and Gao, Lina and Qian, David Z. and Alumkal, Joshi J. and Thomas, Gary and Thomas, George V.. (2011) A HIF-regulated VHL-PTP1B-Src signaling axis identifies a therapeutic target in renal cell carcinoma. Science translational medicine, Vol. 3, H. 85 , 85ra47.

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Official URL: http://edoc.unibas.ch/dok/A6005480

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Abstract

Metastatic renal cell carcinoma (RCC) is a molecularly heterogeneous disease that is intrinsically resistant to chemotherapy and radiotherapy. Although therapies targeted to the molecules vascular endothelial growth factor and mammalian target of rapamycin have shown clinical effectiveness, their effects are variable and short-lived, underscoring the need for improved treatment strategies for RCC. Here, we used quantitative phosphoproteomics and immunohistochemical profiling of 346 RCC specimens and determined that Src kinase signaling is elevated in RCC cells that retain wild-type von Hippel-Lindau (VHL) protein expression. RCC cell lines and xenografts with wild-type VHL exhibited sensitivity to the Src inhibitor dasatinib, in contrast to cell lines that lacked the VHL protein, which were resistant. Forced expression of hypoxia-inducible factor (HIF) in RCC cells with wild-type VHL diminished Src signaling output by repressing transcription of the Src activator protein tyrosine phosphatase 1B (PTP1B), conferring resistance to dasatinib. Our results suggest that a HIF-regulated VHL-PTP1B-Src signaling pathway determines the sensitivity of RCC to Src inhibitors and that stratification of RCC patients with antibody-based profiling may identify patients likely to respond to Src inhibitors in RCC clinical trials.
Faculties and Departments:03 Faculty of Medicine > Bereich Querschnittsfächer (Klinik) > Pathologie USB
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Querschnittsfächer (Klinik) > Pathologie USB
UniBasel Contributors:Schraml, Peter Hans
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:American Association for the Advancement of Science
ISSN:1946-6234
Note:Publication type according to Uni Basel Research Database: Journal article
Identification Number:
Last Modified:27 Feb 2014 15:45
Deposited On:27 Feb 2014 15:45

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