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Updated: Jun 1, 2026

Comparing Metastatic Clear Cell Renal Cell Carcinoma Model Established in Mouse Kidney and on Chicken Chorioallantoic Membrane
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Comparing Metastatic Clear Cell Renal Cell Carcinoma Model Established in Mouse Kidney and on Chicken Chorioallantoic Membrane

Published on: February 8, 2020

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

Natsuko Suwaki1, Elsa Vanhecke, Katelyn M Atkins

  • 1Section of Cell and Molecular Biology, Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK.

Science Translational Medicine
|June 3, 2011
PubMed

Insights

Src kinase signaling drives resistance to targeted therapies in metastatic renal cell carcinoma (RCC). Identifying a VHL-PTP1B-Src pathway offers new strategies for effective RCC treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Signaling

Background:

  • Metastatic renal cell carcinoma (RCC) is challenging to treat due to intrinsic resistance to chemotherapy and radiotherapy.
  • Current targeted therapies (VEGF, mTOR) show variable and transient efficacy, necessitating novel treatment approaches.

Purpose of the Study:

  • To investigate molecular mechanisms underlying treatment resistance in metastatic RCC.
  • To identify predictive biomarkers for Src inhibitor therapy in RCC patients.

Main Methods:

  • Quantitative phosphoproteomics and immunohistochemical profiling of 346 RCC specimens.
  • Assessment of Src inhibitor dasatinib sensitivity in VHL-wild-type and VHL-deficient RCC cell lines and xenografts.
  • Analysis of hypoxia-inducible factor (HIF) effects on Src signaling and dasatinib resistance.

Main Results:

  • Elevated Src kinase signaling was observed in RCC cells with wild-type von Hippel-Lindau (VHL) protein.
  • VHL-wild-type RCC exhibited sensitivity to dasatinib, while VHL-deficient RCC was resistant.
  • Hypoxia-inducible factor (HIF) repressed PTP1B transcription, reducing Src signaling and conferring dasatinib resistance.

Conclusions:

  • A HIF-regulated VHL-PTP1B-Src signaling pathway dictates RCC sensitivity to Src inhibitors.
  • Antibody-based profiling can stratify RCC patients for potential response to Src inhibitors.
  • This pathway provides a basis for developing more effective RCC treatment strategies.

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