Abstract C211: Demonstration of the efficacy of compound CFAK-C4, Targeting FAK-VEGFR-3 protein-protein interaction in animal models of gastric cancer. (2013)

Abstract While the emerging data strongly suggests that FAK is an excellent target for developmental therapeutics of cancer, small molecule kinase inhibitors of FAK have shown crossreactivity with some other protein kinases. We have shown that FAK acts pleiotropically, as a kinase and as a scaffolding protein, to regulate the functions of multiple downstream survival/metastasis/vasculogenesis-related proteins. Therefore, our objective is to target the scaffolding function of FAK to inhibit protein-protein interactions and to yield promising new drug leads. Previously, we have shown that FAK physically interact with VEGFR-3 and both are overexpressed in cancer cells to provide important survival signals. We subsequently identified a novel small molecule inhibitor C4 that targeted this VEGFR-3-FAK site of interaction. Both of these kinases are overexpressed in gastric cancer and were found to be an independent poor prognostic factors. The prognosis of patients with gastric cancer remains unfavorable and molecular based treatments are necessary for a potential breakthrough in the therapy of this disease. We hypothesize that FAK-VEGFR-3 interaction provides essential survival signals for gastric tumor growth and that simultaneous inhibition of these signals will inhibit tumor progression. Using in silico high throughput methods, we screened a chemical library of 240,000 compounds against the known protein-protein interaction site between FAK and VEGFR-3. The ability of one of the lead compounds CFAK-C4 on human gastric cancer cell lines AGS and NCI-N87 were examined by MTT assay (viability), colony formation assay and Western blotting (phosphorylation, apoptosis). Subcutaneous and orthotopic mouse models of gastric cancer were used to demonstrate effect of C4 in vivo. FAK and VEGFR-3 are overexpressed in human gastric cancer cells as determined by Western blotting. C4 specifically blocked phosphorylation of VEGFR-3 and FAK. It directly and significantly (p&amp;lt;0.05) inhibited cell viability, increased cell detachment and inhibited colony formation in a dose-dependent manner (range 1-100μM). C4 (50mg/kg, intraperitoneal injection 5 days a week) effectively caused tumor regression in vivo and effects of C4 were confirmed by a decrease in tumor FAK and VEGFR3 phosphorylation, and disruption of their complexes. In this study, we have shown that CFAK-C4 inhibits FAK-VEGFR3 signaling in gastric cancer cells and affects tumor grows. These results demonstrate that targeting the FAK-VEGFR-3 interaction with a small molecules inhibited the survival function of these two tyrosine kinases, representing a unique approach for molecular-targeted highly-specific cancer therapeutics. Targeting the scaffolding function of FAK with the small-molecule inhibitors can be effectively used to develop potential oral-based gastric cancer therapeutics. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C211. Citation Format: Elena Kurenova, Sartaj Sanghera, Jian Liao, Michael Yemma, William Cance. Demonstration of the efficacy of compound CFAK-C4, Targeting FAK-VEGFR-3 protein-protein interaction in animal models of gastric cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C211.