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

Research output: Contribution to journalArticlepeer-review

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

Keywords

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

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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