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

Kanae Sakakibara, Takayuki Tsujioka, Jun ichiro Kida, Nami Kurozumi, Takako Nakahara, Shin ichiro Suemori, Akira Kitanaka, Yujiro Arao, Kaoru Tohyama

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)213-227
Number of pages15
JournalInternational journal of hematology
Volume110
Issue number2
DOIs
Publication statusPublished - Aug 5 2019

Keywords

  • Akt phosphorylation
  • G arrest
  • Myelodysplastic syndromes (MDS)
  • N-RAS mutation

ASJC Scopus subject areas

  • Hematology

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    Sakakibara, K., Tsujioka, T., Kida, J. I., Kurozumi, N., Nakahara, T., Suemori, S. I., Kitanaka, A., Arao, Y., & Tohyama, K. (2019). Binimetinib, a novel MEK1/2 inhibitor, exerts anti-leukemic effects under inactive status of PI3Kinase/Akt pathway. International journal of hematology, 110(2), 213-227. https://doi.org/10.1007/s12185-019-02667-1