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.
Highlights
With the advent of studies showing patients with KRAS exon 2 mutations (Amado et al, 2008; Karapetis et al, 2008), and extended RAS mutations (KRAS exon 2, 3, 4, and NRAS exon 2, 3, 4) (Douillard et al, 2013; Heinemann et al, 2014), do not derive benefit from treatment with EFGRtargeting monoclonal antibodies, the treatment paradigm for metastatic colorectal cancer (CRC) is shifting to one focused on the molecular subsets of this malignancy
A more pronounced synergistic effect was observed in the KRAS/PIK3CA MT CRC cell lines, with a mean combination index (CI) value of 0.55 ± 0.05, as compared to 53.68 ± 5.48 in the KRAS MT/PIK3CA WT model, 0.89 ± 0.097 in the KRAS WT/PIK3CA WT model, and 0.876 ± 0.077 in the BRAF MT model (Figure 1A)
The KRAS/PIK3CA MT molecular subtype was identified as one of particular interest in the evaluation of alisertib and TAK-733, and a total of nine double-mutant colorectal cancer cell lines were selected for further assessment (Figure 1B)
Summary
With the advent of studies showing patients with KRAS exon 2 mutations (Amado et al, 2008; Karapetis et al, 2008), and extended RAS mutations (KRAS exon 2, 3, 4, and NRAS exon 2, 3, 4) (Douillard et al, 2013; Heinemann et al, 2014), do not derive benefit from treatment with EFGRtargeting monoclonal antibodies, the treatment paradigm for metastatic colorectal cancer (CRC) is shifting to one focused on the molecular subsets of this malignancy. Aurora A kinase-selective inhibitors are known to induce transient mitotic arrest, with the goal of inducing apoptotic cell death in mitosis (Hilton and Shapiro, 2014) Clinical trials with these agents are still in early phases, though no overwhelming single-agent activity in colorectal cancer has yet been noted, and no biomarkers predictive of response to therapy have been identified (Diamond et al, 2011; Cervantes et al, 2012; Dees et al, 2012; Falchook et al, 2014). The specific, targeted mechanism of Aurora A kinase inhibitors makes their use in combination with an agent that may enhance apoptotic activity in cancer cells that have undergone abnormal mitotic progression one of great interest
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