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 language | English |
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Article number | 120 |
Journal | Frontiers in Pharmacology |
Volume | 6 |
Issue number | MAY |
DOIs | |
Publication status | Published - 2015 |
Keywords
- Alisertib
- Aurora A kinase
- Colorectal cancer
- Human tumor xenografts
- KRAS mutation
- MEK
- PIK3CA
- Trametinib
ASJC Scopus subject areas
- Pharmacology
- Pharmacology (medical)