Hepatocyte growth factor (HGF) is an important paracrine mediator of growth, invasion, and angiogenesis in non-small cell lung cancer (NSCLC). We have previously shown that an elevated level of HGF in primary human lung tumor tissues is strongly associated with poor prognosis. HGF acts via its receptor c-Met, a tyrosine kinase receptor, to produce pro-tumorigenic responses. These functions of the HGF/c-Met pathway make it an excellent target for cancer therapeutics. We focused past research on functional actions of HGF/c-Met signaling. In the previous grant period, we demonstrated that the cyclooxygenase-2 (COX-2) pathway was activated in NSCLC cells by HGF. We further showed that HGF induced COX-2 protein via c- Met by activating MAPK and p38. Induction of COX-2 led to increased release of prostaglandin E2 (PGE2), a product of the COX-2 enzyme. We also demonstrated the ability of PGE2 to induce release of ligands for the epidermal growth factor receptor (EGFR) and to cause EGFR-dependent phosphorylation of c-Met, which was HGF-independent. PGE2 induced invasion in NSCLC, which was dependent upon an EGFR-c-Met cross- activation. Combined targeting of the HGF/c-Met and the COX-2 pathway led to maximum reduction in NSCLC invasion induced by HGF. Using a transgenic (TG) mouse that over-expresses human HGF in the airways, we further demonstrated in the last grant period that the increased susceptibility of this TG mouse strain to lung cancer induction by a tobacco carcinogen can be reversed by a neutralizing antibody (NA) to human HGF. Tumors resistant to the HGF NA exhibit a higher rate of K-ras mutation than observed in TG mice treated with an isotope-matched control antibody. This suggests ability to target the HGF/c-Met pathway therapeutically may be less effective in lung tumors with an activating K-ras mutation. In this renewal, we propose to examine the mechanism of signaling interaction between EGFR and c-Met that is initiated by PGE2 (Aim 1). We further propose to examine the extent to which biological effects of EGFR activation such as COX-2 activation, invasion, and wound healing are mediated by an EGFR-c-Met interaction, and whether c-Met and EGFR are co-expressed in human primary lung tumors (Aim 2). We will utilize the HGF TG mouse to determine if combined inhibition of HGF with inhibition of either COX-2 or EGFR results in increased anti-tumor effects, and if K-ras mutant tumors are resistant to these inhibitors (Aim 3). We will produce an immunocompromised mouse strain over-expressing human HGF in the lungs that will support orthotopic growth of human lung tumors. This model will allow pre-clinical study of HGF/c-Met inhibitors on growth of human lung tumors in the presence of elevated human HGF (Aim 4). Research in the pharmaceutical industry is ongoing to produce inhibitors of the HGF/c-Met pathway, which are either in pre-clinical or early Phase I clinical testing. Results from the new aims will provide a mechanistic rationale for the clinical use of inhibitors of the HGF/c-Met pathway alone or in combination with EGFR TKIs or COX-2 inhibitors in treatment of lung cancer.

Public Health Relevance

Lung cancer kills more Americans every year than any other type of cancer. Lung cancer typically is diagnosed at a late stage and does not respond well to current treatments. This project will investigate a new pathway, the HGF/c-Met pathway that controls lung cancer growth. In this project we will test different mechanisms by which the HGF/c-Met pathway controls the activity of other growth-promoting proteins in lung cancer cells, in order to understand how to inhibit this pathway most effectively.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Developmental Therapeutics Study Section (DT)
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Jhappan, Chamelli
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University of Pittsburgh
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Stabile, Laura P; Rothstein, Mary E; Gubish, Christopher T et al. (2014) Co-targeting c-Met and COX-2 leads to enhanced inhibition of lung tumorigenesis in a murine model with heightened airway HGF. J Thorac Oncol 9:1285-93
Dulak, A M; Gubish, C T; Stabile, L P et al. (2011) HGF-independent potentiation of EGFR action by c-Met. Oncogene 30:3625-35
Stabile, Laura P; Rothstein, Mary E; Keohavong, Phouthone et al. (2010) Targeting of Both the c-Met and EGFR Pathways Results in Additive Inhibition of Lung Tumorigenesis in Transgenic Mice. Cancers (Basel) 2:2153-2170
Stabile, Laura P; Rothstein, Mary E; Keohavong, Phouthone et al. (2008) Therapeutic targeting of human hepatocyte growth factor with a single neutralizing monoclonal antibody reduces lung tumorigenesis. Mol Cancer Ther 7:1913-22
Siegfried, Jill M; Gubish, Christopher T; Rothstein, Mary E et al. (2007) Signaling pathways involved in cyclooxygenase-2 induction by hepatocyte growth factor in non small-cell lung cancer. Mol Pharmacol 72:769-79
Stabile, L P; Lyker, J S; Huang, L et al. (2004) Inhibition of human non-small cell lung tumors by a c-Met antisense/U6 expression plasmid strategy. Gene Ther 11:325-35
Siegfried, Jill M; Luketich, James D; Stabile, Laura P et al. (2004) Elevated hepatocyte growth factor level correlates with poor outcome in early-stage and late-stage adenocarcinoma of the lung. Chest 125:116S-9S
Lui, Vivian Wai Yan; Thomas, Sufi Mary; Zhang, Qing et al. (2003) Mitogenic effects of gastrin-releasing peptide in head and neck squamous cancer cells are mediated by activation of the epidermal growth factor receptor. Oncogene 22:6183-93
Stabile, Laura P; Davis, Autumn L Gaither; Gubish, Christopher T et al. (2002) Human non-small cell lung tumors and cells derived from normal lung express both estrogen receptor alpha and beta and show biological responses to estrogen. Cancer Res 62:2141-50
Siegfried, J M (2001) Women and lung cancer: does oestrogen play a role? Lancet Oncol 2:506-13