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Ref Type Journal Article
PMID (19723655)
Authors Antonescu CR, Yoshida A, Guo T, Chang NE, Zhang L, Agaram NP, Qin LX, Brennan MF, Singer S, Maki RG
Title KDR activating mutations in human angiosarcomas are sensitive to specific kinase inhibitors.
Journal Vol Issue Date Pages Journal Short Title
Cancer research 69 18 2009 Sep 15 7175-9 Cancer Res
URL
Abstract Text 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.

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Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
KDR A1065T missense gain of function - predicted KDR (VEGFR2) A1065T lies within the protein kinase domain of the Kdr (Vegfr2) protein (UniProt.org). A1065T results in constitutive tyrosine autophosphorylation (PMID: 19723655), and therefore, is predicted to lead to a gain of Kdr (Vegfr2) protein function.
KDR D717V missense gain of function KDR (VEGFR2) D717V lies within Ig-like C2-type domain 7 of the Kdr (Vegfr2) protein (PMID: 19723655). D717V confers a gain of function to the Kdr (Vegfr2) protein as demonstrated by ligand-independent tyrosine autophosphorylation in cultured cells (PMID: 19723655), and tumor formation in mouse models (PMID: 29588308).
KDR T771R missense unknown KDR (VEGFR2) T771R lies within the transmembrane domain of the Kdr (Vegfr2) protein (UniProt.org). T771R has been identified in the scientific literature (PMID: 26422291, PMID: 19723655, PMID: 32123305), but has not been biochemically characterized and therefore, its effect on Kdr (Vegfr2) protein function is unknown (PubMed, Apr 2026).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
KDR D717V Advanced Solid Tumor sensitive Sunitinib Preclinical - Cell culture Actionable In a preclinical study, cells expressing KDR D717V were sensitive to Sutent (sunitinib) in culture (PMID: 19723655). 19723655
KDR act mut Advanced Solid Tumor sensitive Sorafenib Preclinical Actionable In a preclinical study, Nexavar (sorafenib) demonstrated efficacy in cells expressing KDR activating mutations (PMID: 19723655). 19723655
KDR act mut Advanced Solid Tumor sensitive Sunitinib Preclinical Actionable In a preclinical study, cells expressing KDR activating mutations were sensitive to Sutent (sunitinib) in cell culture (PMID: 19723655). 19723655
KDR A1065T Advanced Solid Tumor sensitive Sunitinib Preclinical Actionable In a preclinical study, cells expressing KDR A1065T were sensitive to Sutent (sunitinib) in culture (PMID: 19723655). 19723655