A HIF-Regulated VHL-PTP1B-Src Signaling Axis Identifies a Therapeutic Target in Renal Cell Carcinoma
2011
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
phosphoproteomicsand 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.
Forcedexpression 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 phosphatase1B (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:
-
Correction
-
Source
-
Cite
-
Save
44
References
49
Citations
NaN
KQI