Binimetinib, a novel MEK1/2 inhibitor, exerts anti-leukemic effects under inactive status of PI3Kinase/Akt pathway
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A MEK1/2 inhibitor, binimetinib is promising as a therapeutic agent for malignant melanoma with N-RAS mutation. We examined in vitro effects of binimetinib on 10 human myeloid/lymphoid leukemia cell 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. Binimetinib inhibited cell growth mainly by inducing G1 arrest and this action mechanism was assisted by gene set enrichment analysis. To identify signaling pathways associated with binimetinib response, 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 binimetinib may not be predicted by the presence/absence of N-RAS mutation, but rather by Akt phosphorylation status. Moreover, combination of binimetinib with a PI3K/Akt inhibitor showed additive growth-suppressive effects. These results suggest that binimetinib shows potential anti-leukemic effects and the basal level of phosphorylated Akt might serve as a biomarker predictive of therapeutic effect.
KeywordsMyelodysplastic syndromes (MDS) N-RAS mutation G1 arrest Akt phosphorylation
This work was supported in part by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science, and in part by a Kawasaki Medical School project grant. The authors thank Ms. Aki Kuyama for editorial assistance.
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Conflict of interest
The authors have no conflict of interest to declare.
- 13.Lee MS, Helms TL, Feng N, Gay J, Chang QE, Tian F, et al. Efficacy of the combination of MEK and CDK4/6 inhibitors in vitro and in vivo in KRAS mutant colorectal cancer models. Oncotarget. 2016;7:39595–608.Google Scholar
- 23.Cancer Cell Line Encyclopedia. https://portals.broadinstitute.org/ccle. Accessed 24 April 2019.
- 29.Gene set enrichment analysis: http://software.broadinstitute.org/gsea/index.jsp. Accessed 24 April 2019.
- 30.Garon EB, Finn RS, Hosmer W, Dering J, Ginther C, Adhami S, et al. Identification of common predictive markers of in vitro response to the Mek inhibitor selumetinib (AZD6244; ARRY-142886) in human breast cancer and non-small cell lung cancer cell lines. Mol Cancer Ther. 2010;9:1985–94.CrossRefGoogle Scholar
- 40.Chen G, Li G. Increased Cul1 expression promotes melanoma cell proliferation through regulating p27 expression. Int J Oncol. 2010;37:1339–44.Google Scholar