title: Combined inhibition of MEK and Aurora A kinase in KRAS/PIK3CA double-mutant colorectal cancer models.
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.
authors.affiliation: 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.
authors.forename: S Lindsey
authors.initials: SL
authors.lastname: Davis
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, University of Colorado Anschutz Medical Campus Aurora, CO, USA.
authors.forename: Kelli M
authors.initials: KM
authors.lastname: Robertson
authors.affiliation: 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.
authors.forename: Todd M
authors.initials: TM
authors.lastname: Pitts
authors.affiliation: 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.
authors.forename: John J
authors.initials: JJ
authors.lastname: Tentler
authors.affiliation: 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.
authors.forename: Erica L
authors.initials: EL
authors.lastname: Bradshaw-Pierce
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, University of Colorado Anschutz Medical Campus Aurora, CO, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Klauck
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, University of Colorado Anschutz Medical Campus Aurora, CO, USA.
authors.forename: Stacey M
authors.initials: SM
authors.lastname: Bagby
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, University of Colorado Anschutz Medical Campus Aurora, CO, USA.
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Hyatt
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, University of Colorado Anschutz Medical Campus Aurora, CO, USA.
authors.forename: Heather M
authors.initials: HM
authors.lastname: Selby
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, University of Colorado Anschutz Medical Campus Aurora, CO, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Spreafico
authors.affiliation: Department of Translational Medicine, Millenium Pharmaceuticals, Inc., A wholly owned Subsidiary of a Takeda Pharmaceutical Company Limited Cambridge, MA, USA.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Ecsedy
authors.affiliation: 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.
authors.forename: John J
authors.initials: JJ
authors.lastname: Arcaroli
authors.affiliation: 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.
authors.forename: Wells A
authors.initials: WA
authors.lastname: Messersmith
authors.affiliation: University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus Aurora, CO, USA.
authors.forename: Aik Choon
authors.initials: AC
authors.lastname: Tan
authors.affiliation: 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.
authors.forename: S Gail
authors.initials: SG
authors.lastname: Eckhardt
keywords: Aurora A kinase; KRAS mutation; MEK; PIK3CA; alisertib; colorectal cancer; human tumor xenografts; trametinib