Research ArticleCancer

A HIF-Regulated VHL-PTP1B-Src Signaling Axis Identifies a Therapeutic Target in Renal Cell Carcinoma

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Science Translational Medicine  01 Jun 2011:
Vol. 3, Issue 85, pp. 85ra47
DOI: 10.1126/scitranslmed.3002004

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Detecting Sensitivity to Src Inhibitors

Typically, tumor suppressors are welcome tenants in cells, protecting them from becoming cancerous. But in a twist of fate, 40% of patients with renal cell carcinoma (RCC) regard the presence of a functional tumor suppressor—the von Hippel-Lindau (VHL) protein—as bad news. And for good reason. In contrast to the other 60% of RCC patients whose tumors are driven by the loss of intact VHL, the tumor-suppressor positive cancers are more likely to be resistant to immunotherapy and chemotherapy, and because researchers do not know what drives tumorigenesis, no rational targeted therapies exist. Not content to wait for another twist of fate, Suwaki et al. have delved deeply into these kidney cancers and found that VHL functions as part of an activated signaling pathway that renders the cells sensitive to anticancer agents that target the Src oncoprotein. The presence of VHL and other markers of this pathway can flag those RCC patients who may benefit from drugs that block Src kinase activity.

Enhanced activity of the Src tyrosine kinase has been implicated in cancer development and is the target of the anticancer drug dasatinib. By measuring the extent of phosphorylation of critical proteins in a pair of cell lines with and without functional VHL, the authors saw that Src and its substrates were activated only when VHL was present. And in 215 RCCs, the presence of VHL tended to be associated with highly active Src kinase. Dasatinib inhibited DNA synthesis and cell growth only in cells with VHL, whether they were grown in culture or as xenografts in mice. The authors also replicated the well-known ability of VHL to negatively regulate the hypoxia-sensitive transcription factor HIF, which is activated indirectly by Src. As expected, expression of HIF in VHL-containing cancer cells conferred resistance to dasatinib. An independent analysis of this pathway in tumor samples from an additional 131 patients with RCC confirmed the positive correlation between VHL and Src and its associated pathway proteins. Here, the authors used quantitative phosphoproteomics and immunohistochemical profiling to show the correlation. Because they used automated digital image analysis and an unsupervised hierarchical clustering of the tumors on the basis of the expression of VHL, Src, pFAK and PTP1B, this approach has the potential to be used in the clinic for tumor characterization.

Personalized approaches to cancer treatment require an armamentarium of matched pairs of drugs and validated biomarkers that predict response to therapy. The markers for an activated Src pathway discerned by the authors could in theory be assessed in any solid cancer; in fact, a test in bladder carcinomas showed that, as in RCCs, the Src pathway proteins were activated. If such a test can be applied to many solid cancers, physicians could use it to predict whether a patient is likely to respond to anti-Src agents.

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).