KDR activating mutations in human angiosarcomas are sensitive to specific kinase inhibitors.
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.
Antonescu
Cristina R
CR
Department of Pathology, Memorial Sloan-Kettering Cancer, New York, New York 10065, USA. antonesc@mskcc.org
Yoshida
Akihiko
A
Guo
Tianhuo
T
Chang
Ning-En
NE
Zhang
Lei
L
Agaram
Narasimhan P
NP
Qin
Li-Xuan
LX
Brennan
Murray F
MF
Singer
Samuel
S
Maki
Robert G
RG
D000818:Animals; D001943:Breast Neoplasms / Q000098:blood supply / Q000201:enzymology / Q000235:genetics; D019556:COS Cells; D002522:Chlorocebus aethiops; D020869:Gene Expression Profiling; D006394:Hemangiosarcoma / Q000098:blood supply / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D009154:Mutation; D009389:Neovascularization, Pathologic / Q000201:enzymology / Q000235:genetics; D010766:Phosphorylation; D014162:Transfection; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
D040301:Vascular Endothelial Growth Factor Receptor-2