Combination of AURKA inhibitor and MEK inhibitor strongly enhances G1 arrest and induces synergistic antitumor effect on KRAS or BRAF mutant colon cancer cells

In colorectal cancer, <i>RAS</i> and <i>BRAF</i> are major mutation points in the RAS-MAPK signaling pathway. These gene mutations are known to be important causes of resistance to anti-EGFR antibody therapies. Recently, it has been reported that Aurora kinase A (AURKA), one of the mitotic kinases, interacts with the EGFR-RAS-MAPK signaling pathway. In this study, we examined whether the combination of MK-5108 (AURKA inhibitor) and trametinib (MEK inhibitor) enhanced the antitumor effect for colon cancer cell lines. The combination of MK-5108 and trametinib showed synergistic enhancements of antitumor effect in three colon cancer cell lines harboring <i>KRAS</i> or <i>BRAF</i> mutation. Cell cycle analysis showed induction of G2/M and G1 arrests by MK-5108 and trametinib, respectively, and the potential enhancement of G1 arrest with the two drug combination. The addition of MK-5108 to trametinib enhanced the suppression of <i>p</i>-ERK and other G1/S progression-related proteins expression. In HCT116 cells, harboring wild-type <i>TP53</i>, the combination therapy induced more potent cell proliferation suppression and apoptosis induction than in <i>TP53</i> knockout cells. These were related to potential enhancement of p53 expression and caspase activation. In conclusion, the combination of MK-5108 and trametinib may synergistically inhibit tumor cell division with or without <i>TP53</i> mutation, and with either <i>KRAS</i> or <i>BRAF</i> mutation. Furthermore, the combination therapy could be more effective in wild-type <i>TP53</i> cells.