Abstract
Recent clinical successes of small-molecule epidermal growth factor receptor (EGFR) inhibitors in treating advanced non-small cell lung cancer (NSCLC) have raised hopes that the identification of other deregulated growth factor pathways in NSCLC will lead to new therapeutic options for NSCLC. Met, the receptor for hepatocyte growth factor, has been implicated in growth, invasion, and metastasis of many tumors including NSCLC. To assess the functional role for Met in NSCLC, we evaluated a panel of nine lung cancer cell lines for Met gene amplification, Met expression, Met pathway activation, and the sensitivity of the cell lines to short hairpin RNA (shRNA)-mediated Met knockdown. Two cell lines, EBC-1 and H1993, showed significant Met gene amplification and overexpressed Met receptors which were constitutively phosphorylated. The other seven lines did not exhibit Met amplification and expressed much lower levels of Met, which was phosphorylated only on addition of hepatocyte growth factor. We also found a strong up-regulation of tyrosine phosphorylation in beta-catenin and p120/delta-catenin in the Met-amplified EBC-1 and H1993 cell lines. ShRNA-mediated Met knockdown induced significant growth inhibition, G(1)-S arrest, and apoptosis in EBC-1 and H1993 cells, whereas it had little or no effect on the cell lines that do not have Met amplification. These results strongly suggest that Met amplification identifies a subset of NSCLC likely to respond to new molecular therapies targeting Met.
Highlights
Lung cancer is one of the most prevalent malignancies and the leading cause of cancer-related mortality in North America and throughout the world
To assess the functional roles of Met in Non–small cell lung cancer (NSCLC), we evaluated a panel of lung cancer cell lines for Met gene amplification, Met expression, Met pathway activation, and the sensitivity of the cell lines to short hairpin RNA–mediated Met knockdown
The high basal phosphorylation at Y1349 was minimally stimulated by hepatocyte growth factor (HGF) (2.5-fold and 1.7-fold in EBC-1 and H1993, respectively), whereas the high levels of Y1234/1235 phosphorylation were not further stimulated by HGF in either cell line
Summary
Lung cancer is one of the most prevalent malignancies and the leading cause of cancer-related mortality in North America and throughout the world. Recent clinical success of epidermal growth factor receptor (EGFR) inhibitors in refractory, advanced NSCLC [2] have raised hopes. Met is a heterodimeric transmembrane receptor tyrosine kinase composed of an extracellular a-chain disulfide-bonded to a membrane-spanning h-chain [3, 4]. Binding of HGF/ SF to Met induces receptor dimerization and trans-phosphorylation, triggering conformational changes that activate Met tyrosine kinase activity [5]. The resultant tyrosine phosphorylation of a multisubstrate docking site, located near the COOH terminus of the Met h-chain, mediates the activation of a number of signaling pathways, including phosphoinositide-3-kinase/phosphoinositide-dependent protein kinase 1/AKT, Ras-Rac/Rho, Ras-mitogen-activated protein kinase, and phospholipase C-g pathways [5]. In addition to proliferative and antiapoptotic activities that are common to many growth factors, HGF/Met elicits unique motogenenic and morphogenic effects by stimulating cell-cell detachment, migration, invasiveness, and tubule formation and branching [5]
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