Binimetinib, a novel MEK1/2 inhibitor, exerts anti-leukemic effects under inactive status of PI3Kinase/Akt pathway

A MEK1/2 inhibitor, binimetinibis promising as a therapeutic agent for malignant melanoma with N-RAS mutation. We examined in vitro effects of binimetinibon 10 human myeloid/ lymphoid leukemiacell lines, and found that three of five cell lines with N-RAS mutation and one of five without N-RAS mutation were responsive to treatment with binimetinib. Binimetinibinhibited cell growth mainly by inducing G1 arrest and this action mechanism was assisted by gene set enrichment analysis. To identify signaling pathways associated with binimetinibresponse, we examined the status of MAP kinase/ERK and PI3Kinase/Akt pathways. The basal levels of phosphorylated ERK and Akt varied between the cell lines, and the amounts of phosphorylated ERK and Akt appeared to be reciprocal of each other. Interestingly, most of the binimetinib-resistant cell lines revealed strong Akt phosphorylation compared with binimetinib-sensitive ones. The effect of binimetinibmay not be predicted by the presence/absence of N-RAS mutation, but rather by Akt phosphorylation status. Moreover, combination of binimetinibwith a PI3K/Akt inhibitor showed additive growth-suppressive effects. These results suggest that binimetinibshows potential anti-leukemic effects and the basal level of phosphorylated Akt might serve as a biomarker predictive of therapeutic effect.