TY - JOUR AU - Davis, S. Lindsey AU - Robertson, Kelli M. AU - Pitts, Todd M. AU - Tentler, John J. AU - Bradshaw-Pierce, Erica L. AU - Klauck, Peter J. AU - Bagby, Stacey M. AU - Hyatt, Stephanie L. AU - Selby, Heather M. AU - Spreafico, Anna AU - Ecsedy, Jeffrey A. AU - Arcaroli, John J. AU - Messersmith, Wells A. AU - Tan, Aik Choon AU - Eckhardt, S. Gail PY - 2015 M3 - Original Research TI - Combined inhibition of MEK and Aurora A kinase in KRAS/PIK3CA double-mutant colorectal cancer models JO - Frontiers in Pharmacology UR - https://www.frontiersin.org/articles/10.3389/fphar.2015.00120 VL - 6 SN - 1663-9812 N2 - Aurora A kinase and MEK inhibitors induce different, and potentially complementary, effects on the cell cycle of malignant cells, suggesting a rational basis for utilizing these agents in combination. In this work, the combination of an Aurora A kinase and MEK inhibitor was evaluated in pre-clinical colorectal cancer models, with a focus on identifying a subpopulation in which it might be most effective. Increased synergistic activity of the drug combination was identified in colorectal cancer cell lines with concomitant KRAS and PIK3CA mutations. Anti-proliferative effects were observed upon treatment of these double-mutant cell lines with the drug combination, and tumor growth inhibition was observed in double-mutant human tumor xenografts, though effects were variable within this subset. Additional evaluation suggests that degree of G2/M delay and p53 mutation status affect apoptotic activity induced by combination therapy with an Aurora A kinase and MEK inhibitor in KRAS and PIK3CA mutant colorectal cancer. Overall, in vitro and in vivo testing was unable to identify a subset of colorectal cancer that was consistently responsive to the combination of a MEK and Aurora A kinase inhibitor. ER -