RRC ID 44366
Author Awazu Y, Nakamura K, Mizutani A, Kakoi Y, Iwata H, Yamasaki S, Miyamoto N, Imamura S, Miki H, Hori A.
Title A novel inhibitor of c-Met and VEGF receptor tyrosine kinases with a broad spectrum of in vivo antitumor activities.
Journal Mol. Cancer Ther.
Abstract The c-Met receptor tyrosine kinase and its ligand, hepatocyte growth factor (HGF), are dysregulated in a wide variety of human cancers and are linked with tumorigenesis and metastatic progression. VEGF also plays a key role in tumor angiogenesis and progression by stimulating the proangiogenic signaling of endothelial cells via activation of VEGF receptor tyrosine kinases (VEGFR). Therefore, inhibiting both HGF/c-Met and VEGF/VEGFR signaling may provide a novel therapeutic approach for treating patients with a broad spectrum of tumors. Toward this goal, we generated and characterized T-1840383, a small-molecule kinase inhibitor that targets both c-Met and VEGFRs. T-1840383 inhibited HGF-induced c-Met phosphorylation and VEGF-induced VEGFR-2 phosphorylation in cancer epithelial cells and vascular endothelial cells, respectively. It also inhibited constitutively activated c-Met phosphorylation in c-met-amplified cancer cells, leading to suppression of cell proliferation. In addition, T-1840383 potently blocked VEGF-dependent proliferation and capillary tube formation of endothelial cells. Following oral administration, T-1840383 showed potent antitumor efficacy in a wide variety of human tumor xenograft mouse models, along with reduction of c-Met phosphorylation levels and microvessel density within tumor xenografts. These results suggest that the efficacy of T-1840383 is produced by direct effects on tumor cell growth and by an antiangiogenic mechanism. Furthermore, T-1840383 showed profound antitumor activity in a gastric tumor peritoneal dissemination model. Collectively, our findings indicate the therapeutic potential of targeting both c-Met and VEGFRs simultaneously with a single small-molecule inhibitor for the treatment of human cancers.
Volume 12(6)
Pages 913-24
Published 2013-6
DOI 10.1158/1535-7163.MCT-12-1011
PII 1535-7163.MCT-12-1011
PMID 23548264
MeSH Angiogenesis Inhibitors / administration & dosage Animals Cell Line, Tumor Cell Proliferation / drug effects Endothelial Cells / drug effects Endothelial Cells / pathology Gene Expression Regulation, Neoplastic / drug effects Hepatocyte Growth Factor / antagonists & inhibitors Hepatocyte Growth Factor / genetics* Heterocyclic Compounds, 2-Ring / administration & dosage* Human Umbilical Vein Endothelial Cells / drug effects Humans Mice Neovascularization, Pathologic / drug therapy Neovascularization, Pathologic / genetics Neovascularization, Pathologic / pathology Niacinamide / administration & dosage Niacinamide / analogs & derivatives* Protein Kinase Inhibitors / administration & dosage* Proto-Oncogene Proteins c-met / antagonists & inhibitors Proto-Oncogene Proteins c-met / genetics* Signal Transduction / drug effects Stomach Neoplasms / blood supply Stomach Neoplasms / drug therapy* Stomach Neoplasms / pathology Vascular Endothelial Growth Factor A / genetics Vascular Endothelial Growth Factor A / metabolism Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors* Vascular Endothelial Growth Factor Receptor-2 / metabolism Xenograft Model Antitumor Assays
IF 4.856
Times Cited 10
Human and Animal Cells