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Front Pharmacol. 2015 Jun 16;6:120. doi: 10.3389/fphar.2015.00120. eCollection 2015.

Combined inhibition of MEK and Aurora A kinase in KRAS/PIK3CA double-mutant colorectal cancer models.

Author information

1
Division of Medical Oncology, Department of Internal Medicine, University of Colorado Anschutz Medical Campus Aurora, CO, USA ; University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus Aurora, CO, USA.
2
Division of Medical Oncology, Department of Internal Medicine, University of Colorado Anschutz Medical Campus Aurora, CO, USA.
3
University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus Aurora, CO, USA ; Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus Aurora, CO, USA ; Department of Drug Metabolism and Pharmacokinetics, Takeda California, Inc. San Diego, CA, USA.
4
Department of Translational Medicine, Millenium Pharmaceuticals, Inc., A wholly owned Subsidiary of a Takeda Pharmaceutical Company Limited Cambridge, MA, USA.
5
University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus Aurora, CO, USA.

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.

KEYWORDS:

Aurora A kinase; KRAS mutation; MEK; PIK3CA; alisertib; colorectal cancer; human tumor xenografts; trametinib

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