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.
NIH ExPorter
NIH ExPorter