Abstract C77: In vivo anticancer activity of an aurora kinase inhibitor, VX-680, in gastric cancer

Abstract

Abstract Background: Aurora kinases (AK) constitute one family of seine/threonine kinases, whose activity is essential for mitotic progression. Expression of aurora kinase is greatest in G2-M phase, and their function includes spindle formation, centrosome maturation, chromosomal segregation, and cytokinesis. Over-expression of AK is related to aneuploidy and carcinogenesis. Herein, we investigated the in vitro and in vivo anticancer acvitivity of a novel AK inhibitor, VX-680 in gastric cancer. Methods: AK protein expression and kinase activity were screened in gastric cancer cell lines using immunoblot and in vitro kinase assay, respectively. The anti-proliferative activity of VX-680 was measured using MTT assay. The changes of cell cycle by the treatment of VX-680 were analyzed by flow cytometry. YCC-16 cell line selected for tumor xenograft models. In vivo activity validation using mouse xenograft models and extract protein or tissue slide from each tumors. Results: AK protein expression and its kinase activity were variable among cell lines. VX-680 showed anti-proliferative effect in vitro on a wide range of gastric cancer cell lines, and calculating the IC50 value, it was distributed from 0.04uM to 19.87uM. It was correlated with kinase activity, not with protein expression of AK. VX-680 induced the reduction of phosphor-histone H3 and the cell cycle defects that accumulated >4N DNA. In vivo experiment, confirmed that AKI had an effect on tumor inhibition. Solid tumor formed with YCC-16 cell lines and VX-680 was injected twice a day for 5 days with a dose of 50mg/kg. Estimating the tumor volume for 21 days after VX-680 injection, the difference in tumor volume between the control and the treated mice were statistically significant. Kinase activity and phospho-histone H3 in VX-680 treated tumor was reduced in drug treatment samples compared to the control samples. Conclusion: We demonstrated that VX-680 has anti-cancer activity in gastric cancer. Kinase activity of AK might be a predictor for sensitivity of VX-680. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C77.