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Expression of oncogenic Kras in the alveolar epithelium is tumorigenic, but the mechanisms of Kras-induced lung tumorigenesis have not been defined. Here we investigated the role of the c-met receptor tyrosine kinase and its ligand, hepatocyte growth factor/scatter factor (HGF/SF), which have been reported to be highly expressed in cancer cells that have mutant KRAS. KrasLA1 mice, which develop multifocal lung adenocarcinomas owing to somatic mutations in KRAS, had high expression of c-met in atypical alveolar hyperplasia (AAH) and adenomas, which precede the development of adenocarcinoma, and high concentrations of HGF/SF in bronchoalveolar lavage samples. Short-term treatment with a small molecule inhibitor of c-met (PHA-00665752) decreased the size of AAH and adenomas and, within these lesions, reduced the phosphorylation of AKT, a pro-survival mediator of c-met, and induced apoptosis of vascular endothelial cells and alveolar epithelial cells. The pro-apoptotic effect of c-met inhibition was observed in vitro in a lung adenocarcinoma cell line derived from KrasLA1 mice and in an immortalized murine vascular endothelial cell line. Thus, c-met activates pro-survival signals in epithelial cells and vascular endothelial cells of early neoplastic lesions and thereby promotes lung tumorigenesis induced by KRAS.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]