Abstract 4045: c-Met inhibition synergistically enhances death receptor-induced apoptosis via upregulation of DR5 in papillary thyroid cancer

Abstract The Met receptor tyrosine kinase and its ligand, hepatocyte growth factor (HGF), are overexpressed and/or activated in variety of human malignancies. Previously we have shown that c-Met was overexpressed in Middle Eastern Papillary Thyroid Cancer (PTC) and significantly associated with poor prognoses. In this study, we investigated the functional link between c-Met/AKT signaling pathway and Dearth Receptor 5 (DR5) in a large cohort of PTC patient samples, a panel of PTC cell lines, and xenografts in a NUDE mouse model by using tissue microarray, MTT, flow cytometry and DNA fragmentation assays and western blotting. Immunohistochemistry staining showed a significant association of p-Met with DR5 in PTC patient samples. The PHA665752, an inhibitor of c-met tyrosine kinase, inhibited cell proliferation and induced apoptosis in a dose dependent manner in all cell lines studied. PHA665752 treatment resulted in dephosphorylation of c-Met, AKT and its downstream effector molecules FOXO1, GSK-3 and pBad. Additionally, treatment of PTC cell lines with PHA665752 resulted in activation of caspases-9 and 3, cleavage PARP and apoptosis. Moreover, HGF, a ligand of c-Met, stimulated the growth of all PTC cell lines via activation of c-MET and AKT. In addition, pre-treatment of PTC cell line with PHA665752 abrogated the HGF stimulated growth and activation of c-met and AKT further suggesting the critical role of c-met and AKT pathway in PTC pathogenesis. Furthermore, c-Met inhibitor PHA665752 up-regulated DR5 expression in PTC cell line cells, and synergistically potentiated death receptor-induced apoptosis with TRAIL. Finally, co-treatment with PHA665752 and TRAIL causes more pronounced effect on PTC xenograft tumor growth in NUDE mice. Our data suggest that c-Met/HGF pathway may be a potential target for therapeutic intervention for treatment of PTC with c-Met inhibitor alone or in combination of conventionally therapeutic agents. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4045. doi:10.1158/1538-7445.AM2011-4045