Inhibition of c-Met as a therapeutic strategy for esophageal adenocarcinoma.

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Inhibition of c-Met as a therapeutic strategy for esophageal adenocarcinoma.
 
Watson GA, Zhang X, Stang MT, Levy RM, Queiroz de Oliveira PE, Gooding WE, Christensen JG, Hughes SJ.
 
Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
 
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-overexpressing EA cell lines (Seg-1, Bic-1, and Flo-1) were
used to examine the effects of a c-Met-specific small molecule
inhibitor (PHA665752) on cell viability, apoptosis, motility, invasion,
and 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.