You are currently viewing the abstract.
View Full TextLog in to view the full text
AAAS login provides access to Science for AAAS members, and access to other journals in the Science family to users who have purchased individual subscriptions.
Register for free to read this article
As a service to the community, this article is available for free. Existing users log in.
More options
Download and print this article for your personal scholarly, research, and educational use.
Buy a single issue of Science for just $15 USD.
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.
Footnotes
-
↵* These authors contributed equally to this work.
-
↵† Present address: Gray Institute for Radiation Oncology and Biology, University of Oxford, Oxford OX3 7DQ, UK.
-
↵‡ Present address: INSERM U981, Institut de Cancérologie Gustave-Roussy, 94805 Villejuif Cedex, France.
-
Citation: N. Suwaki, E. Vanhecke, K. M. Atkins, M. Graf, K. Swabey, P. Huang, P. Schraml, H. Moch, A. M. Cassidy, D. Brewer, B. Al-Lazikani, P. Workman, J. De-Bono, S. B. Kaye, J. Larkin, M. E. Gore, C. L. Sawyers, P. Nelson, T. M. Beer, H. Geng, L. Gao, D. Z. Qian, J. J. Alumkal, G. Thomas, G. V. Thomas, A HIF-Regulated VHL-PTP1B-Src Signaling Axis Identifies a Therapeutic Target in Renal Cell Carcinoma. Sci. Transl. Med. 3, 85ra47 (2011).
- Copyright © 2011, American Association for the Advancement of Science
