Abstract C184: A small molecule FAK inhibitor increases the cytotoxicity of 5-fluorouracil.

Abstract

Abstract Introduction: Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase that has been implicated in colon cancer progression. We have shown that SW620 colon cancer cells express both FAK and activated (phosphorylated) Y397 FAK. 1,2,4,5-Benzenetetraamine tetrahydrochloride (Y15) is a small molecule FAK inhibitor that decreases cell viability and tumor growth in vivo. Because chemotherapy for colon cancer is based upon regimens containing 5-fluorouracil (5-FU), we hypothesized that combining Y15 with 5-FU would synergistically inhibit colon cancer cell viability and growth in vitro and in vivo. Methods: SW620, SW480 and HCT116 colon cancer cells grown in culture were treated with Y15 and 5-FU alone and in combination. In vitro viability was assessed with an MTT assay. To test the in vivo affects of these agents, SW620 cells were injected into the flank of female nude mice. The mice were then treated with either Y15 (100mg/kg oral gavage), 5-FU (30mg/kg intraperitoneal injection), combination Y15+5-FU, or PBS control (30mg/kg intraperitoneal injection). Tumors were measured with calipers every 3 days and tumor volumes calculated. Results: MTT assays demonstrated synergistic inhibition of cell viability with combination Y15+5-FU treatment. The viability of SW620 cells treated with 2microM of Y15 and 50microM of 5-FU was significantly less than that of cells treated with either agent alone (p< 0.05). This trend persisted with dual treatment consisting of 2microM of Y15 and increasing doses of 5-FU (100microM, 200microM, 300microM, p< 0.05). SW480 cells showed similar synergism, with the viability of cells treated with 4microM of Y15 and 50microM of 5-FU significantly less than that of cells treated with either agent alone (p<0.05). Similarly, the viability of HCT116 cells treated with a combination of 500nM of Y15 and 200microM of 5-FU was significantly less than that of cells treated with either agent alone (p<0.05). In vivo, oral gavage Y15 (100mg/kg) and 5-FU (30mg/kg) as single therapies did not inhibit tumor growth. However, mice treated with Y15+5-FU developed tumors that were significantly smaller than single treatment or control groups after 27 days of treatment (p< 0.05). Conclusions: The small molecule FAK inhibitor, Y15, increases the cytotoxic activity of 5-FU against colon cancer cells in vitro. In vivo, at a dose where neither agent decreases tumor growth, the combination of Y15 and 5-FU significantly inhibits tumor growth. These data suggest that Y15 augments the effect of 5-FU and suggests that the addition of this small molecule FAK inhibitor may be a good therapeutic adjunct for treating colon cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C184.