title: Co-targeting c-Met and COX-2 leads to enhanced inhibition of lung tumorigenesis in a murine model with heightened airway HGF.
abstract: BACKGROUND
  The hepatocyte growth factor (HGF)/c-Met pathway is often dysregulated in non-small-cell lung cancer (NSCLC). HGF activation of c-Met induces cyclooxygenase-2 (COX-2), resulting in downstream stimulation by prostaglandin E2 of additional pathways. Targeting both c-Met and COX-2 might lead to enhanced antitumor effects by blocking signaling upstream and downstream of c-Met.
  
  
  METHODS
  Effects of crizotinib or celecoxib alone or in combination were tested in NSCLC cells in vitro and in mice transgenic for airway expression of human HGF.
  
  
  RESULTS
  Proliferation and invasion of NSCLC cells treated with a combination of crizotinib and celecoxib were significantly lower compared with single treatments. Transgenic mice showed enhanced COX-2 expression localized to preneoplastic areas following exposure to the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, which was not present without carcinogen exposure. This shows that COX-2 activity is present during lung tumor development in a high HGF environment. After 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone treatment, a significant decrease in the number of lung tumors per animal was observed after 13-week treatments of crizotinib, celecoxib, or the combination compared with placebo (p < 0.001). With combination treatment, the number of tumors was also significantly lower than single agent treatment (p < 0.001). In the resulting lung tumors, P-c-Met, COX-2, prostaglandin E2, and P-MAPK were significantly downmodulated by combination treatment compared with single treatment. Expression of the epithelial-mesenchymal transition markers E-cadherin and snail was also modulated by combination treatment.
  
  
  CONCLUSIONS
  In the presence of high HGF, dual inhibition of c-Met and COX-2 may enhance antitumor effects. This combination may have clinical potential in NSCLCs with high HGF/c-Met expression or epithelial-mesenchymal transition phenotype.
authors: Departments of *Pharmacology and Chemical Biology and †Biostatistics, University of Pittsburgh, Pittsburgh, Pennsylvania; and ‡Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota.
authors: Laura P
authors: LP
authors: Stabile
authors: Mary E
authors: ME
authors: Rothstein
authors: Christopher T
authors: CT
authors: Gubish
authors: Diana E
authors: DE
authors: Cunningham
authors: Nathan
authors: N
authors: Lee
authors: Jill M
authors: JM
authors: Siegfried
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental; D015398:Signal Transduction
chemical_list: D004273:DNA, Neoplasm; C066855:HGF protein, human; D017228:Hepatocyte Growth Factor; D051546:Cyclooxygenase 2