Abstract 2026: Co-targeting c-Met and COX-2 leads to enhanced inhibition of lung tumorigenesis in a murine model with heightened HGF signaling in the airways.
Authors: Stabile Laura P. , Rothstein Mary E. , Gubish Christopher T. , Lee Nathan , Cunningham Diana E. , Siegfried Jill M. 
Published: August 2014

The hepatocyte growth factor (HGF)/c-Met signaling pathway is often dysregulated in lung cancer. We previously showed that HGF activation of c-Met in non-small cell lung cancer (NSCLC) cells led to a significant induction of cyclooxygenase-2 (COX-2) followed by secretion of PGE2. PGE2 caused secretion of TGFα by NSCLC cells, followed by both phosphorylation of EGFR and later, delayed phosphorylation of c-Met that does not require HGF. Secretion of PGE2 also appears to boost c-Met pathway signaling downstream via cross-activation by EGFR, in a reinforcing loop that is independent of HGF. We hypothesized that targeting of both c-Met and COX-2 might lead to enhanced anti-tumor effects by blocking both upstream and downstream pro-tumor events. Maximum effects on cell proliferation, invasion and EMT markers were observed in vitro in NSCLC cell lines with combination celecoxib and crizotinib treatment. We next tested whether targeting c-Met with the tyrosine kinase inhibitor crizotinib combined with celecoxib to target COX-2 would result in enhanced anti-tumor effects in an animal model with heightened HGF/c-Met pathway signaling in the airways. Mice transgenic for airway expression of human HGF were treated with the tobacco carcinogen, 4-(methylnitroso-amino)-1-(3-pyridyl)-1-butanone, from weeks 1-4. Crizotinib (40mg/kg), celecoxib (50mg/kg), combined crizotinib and celecoxib or placebo control was administered by oral gavage daily from week 3 until week 15, at which time lung tumors were evaluated. A highly significant decrease in the number of lung tumors per animal was observed with crizotinib treatment (mean 3.6, range 2-6), celecoxib treatment (mean 4.3, range 3-6) and combination treatment (mean 1.5, range 0-3) compared to placebo control (mean 9.9, range 6-13; P&lt;0.001, Poisson regression). The number of tumors in the combination treatment group was also significantly lower than either single agent treatment (P&lt;0.001). There was also a significant decrease in mean tumor size with crizotinib (mean 0.20mm2), celecoxib (mean 0.22mm2) and combination (mean 0.15mm2) compared to placebo (mean 0.38mm2, P&lt;0.001, mixed effects modeling). Three biomarkers (COX-2, PGE2, and P-MAPK) were optimally down-modulated by combination treatment, compared to single treatment. Additionally, E-cadherin expression was up-regulated while the E-cadherin repressor, snail, was down-regulated with dual treatment. In a pulmonary environment with heightened HGF/c-Met pathway activity, dual inhibition of the c-Met and COX-2 pathways may enhance anti-tumor effects by targeting reinforcing up- and downstream signaling. Such a combination has potential clinical benefit for lung cancer patients with dysregulated c-Met/COX-2 pathways. Supported by R01 CA79882 and P50 CA090440.

Citation Format: Laura P. Stabile, Mary E. Rothstein, Christopher T. Gubish, Nathan Lee, Diana E. Cunningham, Jill M. Siegfried. Co-targeting c-Met and COX-2 leads to enhanced inhibition of lung tumorigenesis in a murine model with heightened HGF signaling in the airways. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2026. doi:10.1158/1538-7445.AM2013-2026