Abstract
The c-Met receptor tyrosine kinase is emerging as a novel target in many solid tumors, including lung cancer. PHA-665752 was identified as a small molecule, ATP competitive inhibitor of the catalytic activity of the c-Met kinase. Here, we show that treatment with PHA665752 reduced NCI-H69 (small cell lung cancer) and NCI-H441 (non-small cell lung cancer) tumorigenicity in mouse xenografts by 99% and 75%, respectively. Reduction in tumor size was also observed by magnetic resonance imaging of tumors in mice. PHA665752 inhibited c-Met phosphorylation at the autophosphorylation and c-Cbl binding sites in mouse xenografts derived from non-small cell lung cancer cell lines (NCI-H441 and A549) and small cell lung cancer cell line (NCI-H69). PHA665752 also inhibited angiogenesis by >85% in all the abovementioned cell lines and caused an angiogenic switch which resulted in a decreased production of vascular endothelial growth factor and an increase in the production of the angiogenesis inhibitor thrombospondin-1. These studies show the feasibility of selectively targeting c-Met with ATP competitive small molecule inhibitors and suggest that PHA665752 may provide a novel therapeutic approach to lung cancer.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Carcinoma, Non-Small-Cell Lung / blood supply
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Carcinoma, Non-Small-Cell Lung / drug therapy*
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Carcinoma, Non-Small-Cell Lung / enzymology
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Carcinoma, Non-Small-Cell Lung / pathology
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Carcinoma, Small Cell / blood supply
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Carcinoma, Small Cell / drug therapy*
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Carcinoma, Small Cell / enzymology
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Carcinoma, Small Cell / pathology
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Cell Growth Processes / drug effects
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Cell Line, Tumor
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Humans
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Immunohistochemistry
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Indoles / pharmacology*
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Lung Neoplasms / blood supply
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Lung Neoplasms / drug therapy*
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Lung Neoplasms / enzymology
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Lung Neoplasms / pathology
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Male
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Mice
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Mice, Nude
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Neovascularization, Pathologic / drug therapy
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Neovascularization, Pathologic / metabolism
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Neovascularization, Pathologic / pathology
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Proto-Oncogene Proteins c-met / antagonists & inhibitors*
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Sulfones / pharmacology*
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Thrombospondin 1 / biosynthesis
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Vascular Endothelial Growth Factor A / biosynthesis
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Xenograft Model Antitumor Assays
Substances
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5-((2,6-dichlorobenzyl)sulfonyl)-3-((3,5-dimethyl-4-((2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-1,3-dihydro-2H-indol-2-one
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Indoles
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Sulfones
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Thrombospondin 1
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Vascular Endothelial Growth Factor A
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Proto-Oncogene Proteins c-met