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

Natsuko Suwaki, Elsa Vanhecke, Katelyn M. Atkins, Manuela Graf, Katherine Swabey, Paul Huang, Peter Schraml, Holger Moch, Amy Mulick Cassidy, Daniel Brewer, Bissan Al-Lazikani, Paul Workman, Johann De-Bono, Stan B. Kaye, James Larkin, Martin E. Gore, Charles L. Sawyers, Peter Nelson, Tomasz (Tom) Beer, Hao GengLina Gao, Zheng (David) Qian, Joshi Alumkal, Gary Thomas, George Thomas

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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.

Original languageEnglish (US)
Article number85ra47
JournalScience Translational Medicine
Volume3
Issue number85
DOIs
StatePublished - Jun 1 2011

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Non-Receptor Type 1 Protein Tyrosine Phosphatase
Renal Cell Carcinoma
Therapeutics
Hypoxia
Cell Line
src-Family Kinases
Sirolimus
Heterografts
Vascular Endothelial Growth Factor A
Proteins
Radiotherapy
Clinical Trials

ASJC Scopus subject areas

  • Medicine(all)

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

In: Science Translational Medicine, Vol. 3, No. 85, 85ra47, 01.06.2011.

Research output: Contribution to journalArticle

Suwaki, N, Vanhecke, E, Atkins, KM, Graf, M, Swabey, K, Huang, P, Schraml, P, Moch, H, Cassidy, AM, Brewer, D, Al-Lazikani, B, Workman, P, De-Bono, J, Kaye, SB, Larkin, J, Gore, ME, Sawyers, CL, Nelson, P, Beer, TT, Geng, H, Gao, L, Qian, ZD, Alumkal, J, Thomas, G & Thomas, G 2011, 'A HIF-regulated VHL-PTP1B-Src signaling axis identifies a therapeutic target in renal cell carcinoma', Science Translational Medicine, vol. 3, no. 85, 85ra47. https://doi.org/10.1126/scitranslmed.3002004
Suwaki, Natsuko ; Vanhecke, Elsa ; Atkins, Katelyn M. ; Graf, Manuela ; Swabey, Katherine ; Huang, Paul ; Schraml, Peter ; Moch, Holger ; Cassidy, Amy Mulick ; Brewer, Daniel ; Al-Lazikani, Bissan ; Workman, Paul ; De-Bono, Johann ; Kaye, Stan B. ; Larkin, James ; Gore, Martin E. ; Sawyers, Charles L. ; Nelson, Peter ; Beer, Tomasz (Tom) ; Geng, Hao ; Gao, Lina ; Qian, Zheng (David) ; Alumkal, Joshi ; Thomas, Gary ; Thomas, George. / A HIF-regulated VHL-PTP1B-Src signaling axis identifies a therapeutic target in renal cell carcinoma. In: Science Translational Medicine. 2011 ; Vol. 3, No. 85.
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AU - Graf, Manuela

AU - Swabey, Katherine

AU - Huang, Paul

AU - Schraml, Peter

AU - Moch, Holger

AU - Cassidy, Amy Mulick

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AU - De-Bono, Johann

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AU - Larkin, James

AU - Gore, Martin E.

AU - Sawyers, Charles L.

AU - Nelson, Peter

AU - Beer, Tomasz (Tom)

AU - Geng, Hao

AU - Gao, Lina

AU - Qian, Zheng (David)

AU - Alumkal, Joshi

AU - Thomas, Gary

AU - Thomas, George

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N2 - 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.

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