Combination of CYP inhibitor with MEK/ERK inhibitor enhances the inhibitory effect on ERK in BRAF mutant colon cancer cells.

Abstract

BACKGROUND/AIM: To investigate mechanisms of discrepancy in response to a MEK/ERK inhibitor, U0126, in KRAS- and BRAF-mutant colorectal cancer cells. MATERIALS AND METHODS: Multiparametric flow cytometry was performed on two colon cancer cell lines, HCT116 and HT29. Cells were treated with U0126, and phospho-specific antibodies were used to monitor ERK signaling. RESULTS: HCT116 and HT29 cells were treated with increasing amounts of U0126. The western blot analysis revealed that by increasing the amount of U0126 resulted in inhibition of phospho-ERK, in HCT116 and to a lesser degree in HT29 cells. Microarray profiling identified CYP1A1 and 1A2 overexpression in HT29 cells and that inhibition of CYP1A1 with α-naphthoflavone and furanfylline restored sensitivity to U0126 in HT29 cells. CONCLUSION: Combination of a CYP inhibitor with MEK/ERK inhibitor enhances the inhibitory effect on ERK in BRAF-mutant colon cancer cells.