A HIF-regulated VHL-PTP1B-Src signaling axis identifies a therapeutic target in renal cell carcinoma Journal Article
| Authors: | Suwaki, N.; Vanhecke, E.; Atkins, K. M.; Graf, M.; Swabey, K.; Huang, P.; Schraml, P.; Moch, H.; Cassidy, A. M.; Brewer, D.; Al-Lazikani, B.; Workman, P.; de Bono, J.; Kaye, S. B.; Larkin, J.; Gore, M. E.; Sawyers, C. L.; Nelson, P.; Beer, T. M.; Geng, H.; Gao, L.; Qian, D. Z.; Alumkal, J. J.; Thomas, G.; Thomas, G. V. |
| Article Title: | A HIF-regulated VHL-PTP1B-Src signaling axis identifies a therapeutic target in renal cell carcinoma |
| 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. |
| Keywords: | immunohistochemistry; signal transduction; controlled study; human tissue; protein expression; major clinical study; nonhuman; drug targeting; mouse; animal experiment; animal model; antineoplastic activity; cancer cell culture; tumor xenograft; drug effect; dasatinib; protein tyrosine kinase; proteomics; wild type; kidney carcinoma; cancer resistance; hypoxia inducible factor; drug sensitivity; von hippel lindau protein; protein tyrosine phosphatase 1b |
| Journal Title: | Science Translational Medicine |
| Volume: | 3 |
| Issue: | 85 |
| ISSN: | 1946-6234 |
| Publisher: | American Association for the Advancement of Science |
| Date Published: | 2011-06-01 |
| Start Page: | 85ra47 |
| Language: | English |
| DOI: | 10.1126/scitranslmed.3002004 |
| PROVIDER: | scopus |
| PUBMED: | 21632985 |
| PMCID: | PMC3303496 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 23 June 2011" - "Art. No.: 85ra47" - "Source: Scopus" |
