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

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

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13 Citations (Scopus)

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.

Original languageEnglish
Article number120
JournalFrontiers in Pharmacology
Volume6
Issue numberMAY
DOIs
Publication statusPublished - 2015
Externally publishedYes

Keywords

  • Alisertib
  • Aurora A kinase
  • Colorectal cancer
  • Human tumor xenografts
  • KRAS mutation
  • MEK
  • PIK3CA
  • Trametinib

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology

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  • Cite this

    Lindsey Davis, S., Robertson, K. M., Pitts, T. M., Tentler, J. J., Bradshaw-Pierce, E. L., Klauck, P. J., Bagby, S. M., Hyatt, S. L., Selby, H. M., Spreafico, A., Ecsedy, J. A., Arcaroli, J. J., Messersmith, W. A., Tan, A-C., & Gail Eckhardt, S. (2015). Combined inhibition of MEK and Aurora A kinase in KRAS/PIK3CA double-mutant colorectal cancer models. Frontiers in Pharmacology, 6(MAY), [120]. https://doi.org/10.3389/fphar.2015.00120