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

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. (September 2009) KDR activating mutations in human angiosarcomas are sensitive to specific kinase inhibitors. Cancer Res, 69 (18). pp. 7175-9. ISSN 1538-7445 (Electronic)0008-5472 (Linking)

URL: https://www.ncbi.nlm.nih.gov/pubmed/19723655
DOI: 10.1158/0008-5472.CAN-09-2068

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 show distinct 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.

Item Type: Paper
Uncontrolled Keywords: Animals Breast Neoplasms/blood supply/enzymology/genetics COS Cells Cercopithecus aethiops Gene Expression Profiling Hemangiosarcoma/blood supply/enzymology/*genetics Humans *Mutation Neovascularization, Pathologic/enzymology/genetics Phosphorylation Transfection Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors/*genetics/metabolism
Subjects: diseases & disorders > cancer > drugs and therapies
diseases & disorders > cancer > cancer types > sarcoma
CSHL Authors:
Communities: CSHL labs > Maki lab
Depositing User: Matt Covey
Date: 15 September 2009
Date Deposited: 26 Oct 2016 15:14
Last Modified: 26 Oct 2016 15:14
PMCID: PMC2763376
Related URLs:
URI: http://repository.cshl.edu/id/eprint/33693

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