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.
authors.affiliation: Section of Cell and Molecular Biology, Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK.
authors.forename: Natsuko
authors.initials: N
authors.lastname: Suwaki
authors.forename: Elsa
authors.initials: E
authors.lastname: Vanhecke
authors.forename: Katelyn M
authors.initials: KM
authors.lastname: Atkins
authors.forename: Manuela
authors.initials: M
authors.lastname: Graf
authors.forename: Katherine
authors.initials: K
authors.lastname: Swabey
authors.forename: Paul
authors.initials: P
authors.lastname: Huang
authors.forename: Peter
authors.initials: P
authors.lastname: Schraml
authors.forename: Holger
authors.initials: H
authors.lastname: Moch
authors.forename: Amy Mulick
authors.initials: AM
authors.lastname: Cassidy
authors.forename: Daniel
authors.initials: D
authors.lastname: Brewer
authors.forename: Bissan
authors.initials: B
authors.lastname: Al-Lazikani
authors.forename: Paul
authors.initials: P
authors.lastname: Workman
authors.forename: Johann
authors.initials: J
authors.lastname: De-Bono
authors.forename: Stan B
authors.initials: SB
authors.lastname: Kaye
authors.forename: James
authors.initials: J
authors.lastname: Larkin
authors.forename: Martin E
authors.initials: ME
authors.lastname: Gore
authors.forename: Charles L
authors.initials: CL
authors.lastname: Sawyers
authors.forename: Peter
authors.initials: P
authors.lastname: Nelson
authors.forename: Tomasz M
authors.initials: TM
authors.lastname: Beer
authors.forename: Hao
authors.initials: H
authors.lastname: Geng
authors.forename: Lina
authors.initials: L
authors.lastname: Gao
authors.forename: David Z
authors.initials: DZ
authors.lastname: Qian
authors.forename: Joshi J
authors.initials: JJ
authors.lastname: Alumkal
authors.forename: Gary
authors.initials: G
authors.lastname: Thomas
authors.forename: George V
authors.initials: GV
authors.lastname: Thomas
mesh_terms: D002292:Carcinoma, Renal Cell / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000069439:Dasatinib; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D066298:In Vitro Techniques; D047428:Protein Kinase Inhibitors; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D019061:src-Family Kinases; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D000069439:Dasatinib