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

Abstract

In colorectal cancer, RAS and BRAF 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 KRAS or BRAF 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 p-ERK and other G1/S progression-related proteins expression. In HCT116 cells, harboring wild-type TP53, the combination therapy induced more potent cell proliferation suppression and apoptosis induction than in TP53 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 TP53 mutation, and with either KRAS or BRAF mutation. Furthermore, the combination therapy could be more effective in wild-type TP53 cells.