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International journal of hematology
Aug, 2019;110 (2): 213-227.

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
Author Information
  1. Kanae Sakakibara: Division of Medical Technology, Kawasaki University of Medical Welfare, Okayama, 701-0192, Japan.
  2. Takayuki Tsujioka: Department of Laboratory Medicine, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama, 701-0192, Japan.
  3. Jun-Ichiro Kida: Department of Laboratory Medicine, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama, 701-0192, Japan.
  4. Nami Kurozumi: Division of Medical Technology, Kawasaki University of Medical Welfare, Okayama, 701-0192, Japan.
  5. Takako Nakahara: Division of Medical Technology, Kawasaki University of Medical Welfare, Okayama, 701-0192, Japan.
  6. Shin-Ichiro Suemori: Department of Laboratory Medicine, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama, 701-0192, Japan.
  7. Akira Kitanaka: Division of Medical Technology, Kawasaki University of Medical Welfare, Okayama, 701-0192, Japan.
  8. Yujiro Arao: Field of Medical Technology, Graduate School of Health Sciences, Okayama University, Okayama, 700-8558, Japan.
  9. Kaoru Tohyama: Division of Medical Technology, Kawasaki University of Medical Welfare, Okayama, 701-0192, Japan. ktohyama@med.kawasaki-m.ac.jp. ORCID
PMID: 31129802 DOI: 10.1007/s12185-019-02667-1

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 G 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.

Keywords

Akt phosphorylation G1 arrest Myelodysplastic syndromes (MDS) N-RAS mutation

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MeSH Term

Aminopyridines
Antineoplastic Agents
Apoptosis
Benzimidazoles
Cell Cycle
Cell Line, Tumor
DNA, Neoplasm
Drug Resistance, Neoplasm
Drug Screening Assays, Antitumor
G1 Phase
Gene Expression Regulation, Leukemic
Genes, ras
Humans
Leukemia
MAP Kinase Signaling System
Morpholines
Mutation
Neoplasm Proteins
Oncogene Protein p21(ras)
Phosphatidylinositol 3-Kinases
Phosphorylation
Protein Kinase Inhibitors
Protein Processing, Post-Translational
Proto-Oncogene Proteins c-akt
Signal Transduction

Chemicals

Aminopyridines
Antineoplastic Agents
Benzimidazoles
DNA, Neoplasm
Morpholines
NVP-BKM120
Neoplasm Proteins
Protein Kinase Inhibitors
binimetinib
Proto-Oncogene Proteins c-akt
Oncogene Protein p21(ras)
Journal Article

Word Cloud

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