Co-targeting c-Met and COX-2 leads to enhanced inhibition of lung tumorigenesis in a murine model with heightened airway HGF

Laura P. Stabile, Mary E. Rothstein, Christopher T. Gubish, Diana E. Cunningham, Nathan Lee, Jill M. Siegfried

Research output: Contribution to journalArticle

3 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1285-1293
Number of pages9
JournalJournal of Thoracic Oncology
Volume9
Issue number9
DOIs
StatePublished - Sep 2014

Keywords

  • COX-2
  • Celecoxib
  • Crizotinib
  • HGF
  • Lung cancer
  • c-Met

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