Title |
Combined inhibition of MEK and Aurora A kinase in KRAS/PIK3CA double-mutant colorectal cancer models
|
---|---|
Published in |
Frontiers in Pharmacology, June 2015
|
DOI | 10.3389/fphar.2015.00120 |
Pubmed ID | |
Authors |
S. Lindsey Davis, Kelli M. Robertson, Todd M. Pitts, John J. Tentler, Erica L. Bradshaw-Pierce, Peter J. Klauck, Stacey M. Bagby, Stephanie L. Hyatt, Heather M. Selby, Anna Spreafico, Jeffrey A. Ecsedy, John J. Arcaroli, Wells A. Messersmith, Aik Choon Tan, S. Gail Eckhardt |
Abstract |
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. |
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