Abstract B173: Synergistic interaction between CENP-E inhibitor GSK923295 and MEK inhibitor GSK1120212

Centromere protein-E (CENP-E) is a mitotic kinesin that is required during mitosis for metaphase chromosome alignment. GSK923295 (′295) is a potent and specific inhibitor of human CENP-E currently being developed as a next generation antimitotic drug for the treatment of cancer. It has shown a broad spectrum of anti-cancer activity in vitro and in vivo. A siRNA library screen targeting the ‘druggable genome’ identified multiple MAPK pathway genes as sensitizers to ′295, including BRAF and ERK1. Since the MEK protein plays an important role in the MAPK pathway, combination studies between GSK MEK inhibitor GSK1120212 (′212) and ′295 were performed in cancer cell lines from different tissue origins, and the combination effect was evaluated based on three different criteria: Excess over Single Highest Agent (EOHSA), Bliss, and Combination Index (CI).. Synergistic response was observed in 5/6 colon cancer cell lines, 5/15 lung cancer cell lines, and 6/8 pancreas cancer cell lines. Additionally, the combination of ′212 and ′295 treatment induced a much stronger apoptotic response than either drug alone in two colon cancer cell lines. These data suggest that combining MEK and CENP-E inhibitors might improve clinical efficacy over either as a single agent in selected tumors. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B173.