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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Watson, GA; Zhang, X; Stang, MT; Levy, RM; Queiroz de Oliveira, PE; Gooding, WE; Christensen, JG; Hughes, SJ

Published Date

  • November 2006

Published In

Volume / Issue

  • 8 / 11

Start / End Page

  • 949 - 955

PubMed ID

  • 17132227

Pubmed Central ID

  • PMC1716014

Electronic International Standard Serial Number (EISSN)

  • 1476-5586

Digital Object Identifier (DOI)

  • 10.1593/neo.06499


  • eng

Conference Location

  • United States