KDR activating mutations in human angiosarcomas are sensitive to specific kinase inhibitors Journal Article

Authors: Antonescu, C. R.; Yoshida, A.; Guo, T.; Chang, N. E.; Zhang, L.; Agaram, N. P.; Qin, L. X.; Brennan, M. F.; Singer, S.; Maki, R. G.
Article Title: KDR activating mutations in human angiosarcomas are sensitive to specific kinase inhibitors
Abstract: Angiosarcomas (AS) represent a heterogeneous group of malignant vascular tumors occurring not only in different anatomic locations but also in distinct clinical settings, such as radiation or associated chronic lymphedema. Although representing only 1% to 2% of soft tissue sarcomas, vascular sarcomas provide unique insight into the general process of tumor angiogenesis. However, no molecular candidates have been identified to guide a specific therapeutic intervention. By expression profiling, AS showdis tinct up-regulation of vascular-specific receptor tyrosine kinases, including TIE1, KDR, SNRK, TEK, and FLT1. Full sequencing of these five candidate genes identified 10% of patients harboring KDR mutations. A KDR-positive genotype was associated with strong KDR protein expression and was restricted to the breast anatomic site with or without prior exposure to radiation. Transient transfection of KDR mutants into COS-7 cells showed ligand-independent activation of the kinase, which was inhibited by specific KDR inhibitors. These data provide a basis for the activity of vascular endothelial growth factor receptor-directed therapy in the treatment of primary and radiation-induced AS. ©2009 American Association for Cancer Research.
Keywords: vasculotropin; clinical article; controlled study; human tissue; protein expression; protein phosphorylation; gene mutation; mutation; animals; gene expression profiling; genotype; transfection; tyrosine; vasculotropin inhibitor; vasculotropin receptor 2; angiogenesis; angiosarcoma; autophosphorylation; cell strain cos7; immunoreactivity; mutational analysis; radiation injury; breast neoplasms; cercopithecus aethiops; cos cells; hemangiosarcoma; neovascularization, pathologic; phosphorylation; vascular endothelial growth factor receptor-2
Journal Title: Cancer Research
Volume: 69
Issue: 18
ISSN: 0008-5472
Publisher: American Association for Cancer Research  
Date Published: 2009-09-15
Start Page: 7175
End Page: 7179
Language: English
DOI: 10.1158/0008-5472.can-09-2068
PUBMED: 19723655
PROVIDER: scopus
PMCID: PMC2763376
Notes: --- - "Cited By (since 1996): 5" - "Export Date: 30 November 2010" - "CODEN: CNREA" - "Source: Scopus"
Altmetric Score
MSK Authors
  1. Murray F Brennan
    782 Brennan
  2. Narasimhan P Agaram
    117 Agaram
  3. Cristina R Antonescu
    612 Antonescu
  4. Robert Maki
    211 Maki
  5. Li-Xuan Qin
    116 Qin
  6. Samuel Singer
    233 Singer
  7. Tianhua Guo
    22 Guo
  8. Lei Zhang
    136 Zhang
  9. Ning-En Chang
    6 Chang