International Journal of Hematology

, Volume 110, Issue 2, pp 213–227 | Cite as

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 TohyamaEmail author
Original Article


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.


Myelodysplastic 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.

Compliance with ethical standards

Conflict of interest

The authors have no conflict of interest to declare.

Supplementary material

12185_2019_2667_MOESM1_ESM.jpg (942 kb)
Binimetinib inhibits the proliferation of some leukemia cell lines. Five cell lines with N-RAS mutation (HL-60, MDS-L, TF-1, THP-1 and MOLT4) and five cell lines without this mutation (Jurkat, K562, U937, MOLM13 and F-36P) were treated with binimetinib (0-1 µM) for indicated times (24, 48, 72 and 96 h) and cell growth was assessed by trypan blue staining. The value without binimetinib was adjusted to 100%. The data represent the mean values with SD from three independent experiments (JPEG 941 kb)
12185_2019_2667_MOESM2_ESM.jpg (147 kb)
Buparlisib inhibits the proliferation of TF-1 and F-36P cell lines. TF-1 and F-36P were treated with 1 µM buparlisib for 48 h and cell count was evaluated by trypan blue staining (JPEG 146 kb)


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Copyright information

© Japanese Society of Hematology 2019

Authors and Affiliations

  1. 1.Division of Medical TechnologyKawasaki University of Medical WelfareOkayamaJapan
  2. 2.Field of Medical Technology, Graduate School of Health SciencesOkayama UniversityOkayamaJapan
  3. 3.Department of Laboratory MedicineKawasaki Medical SchoolKurashikiJapan

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