Inhibition of c-Met as a Therapeutic Strategy for Esophageal Adenocarcinoma

The hepatocyte growth factor (HGF) receptor c-Met is a tyrosine kinase receptor with established oncogenic properties. We have previously shown that c-Met is usually overexpressed in esophageal adenocarcinoma (EA), yet the implications of c-Met inhibition in EA remain unknown. Three c-Met-overexpres...

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Veröffentlicht in:Neoplasia (New York, N.Y.) N.Y.), 2006-11, Vol.8 (11), p.949-955
Hauptverfasser: Watson, Gregory A., Zhang, Xinglu, Stang, Michael T., Levy, Ryan M., Queiroz de Oliveira, Pierre E., Gooding, William E., Christensen, James G., Hughes, Steven J.
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Sprache:eng
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Zusammenfassung:The hepatocyte growth factor (HGF) receptor c-Met is a tyrosine kinase receptor with established oncogenic properties. We have previously shown that c-Met is usually overexpressed in esophageal adenocarcinoma (EA), yet the implications of c-Met inhibition in EA remain unknown. Three c-Met-overexpressiog EA cell lines (Seg-1, Bic-1, Flo-1) were used to examine the effects of a c-Met-specific small molecule inhibitor (PHA665752) on cell viability, apoptosis, motility, invasion, downstream signaling pathways. PHA665752 demonstrated dose-dependent inhibition of constitutive and/or HGF-induced phosphorylation of c-Met, which correlated with reduced cell viability and inhibition of extracellular regulated kinase 1/2 phosphorylation in all three EA cell lines. In contrast, PHA665752 induced apoptosis and reduced motility and invasion in only one EA cell line, Flo-1. Interestingly, Flo-1 was the only cell line in which phosphatidylinositol 3-kinase (PI3K)/Akt was induced following HGF stimulation. The PI3K inhibitor LY294002 produced effects equivalent to those of PHA665752 in these cells. We conclude that inhibition of c-Met may be a useful therapeutic strategy for EA. Factors other than receptor overexpression, such as c-Met-dependent PI3K/Akt signaling, may be predictive of an individual tumor's response to c-Met inhibition.
ISSN:1476-5586
1522-8002
1476-5586
1522-8002
DOI:10.1593/neo.06499