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
JournalInternational journal of hematology
DOIs
Publication statusPublished - Jan 1 2019

Fingerprint

Cell Line
Mutation
Phosphorylation
MEK162
Lymphoid Leukemia
Myeloid Leukemia
Therapeutic Uses
Growth
Phosphatidylinositol 3-Kinases
Melanoma
Phosphotransferases
Biomarkers
Lymphocytes
Genes
Therapeutics
In Vitro Techniques

Keywords

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

ASJC Scopus subject areas

  • Hematology

Cite this

Binimetinib, a novel MEK1/2 inhibitor, exerts anti-leukemic effects under inactive status of PI3Kinase/Akt pathway. / Sakakibara, Kanae; Tsujioka, Takayuki; Kida, Jun ichiro; Kurozumi, Nami; Nakahara, Takako; Suemori, Shin ichiro; Kitanaka, Akira; Arao, Yujiro; Tohyama, Kaoru.

In: International journal of hematology, 01.01.2019.

Research output: Contribution to journalArticle

Sakakibara, Kanae ; Tsujioka, Takayuki ; Kida, Jun ichiro ; Kurozumi, Nami ; Nakahara, Takako ; Suemori, Shin ichiro ; Kitanaka, Akira ; Arao, Yujiro ; Tohyama, Kaoru. / Binimetinib, a novel MEK1/2 inhibitor, exerts anti-leukemic effects under inactive status of PI3Kinase/Akt pathway. In: International journal of hematology. 2019.
@article{da20e5c906b24efa8d788647a86da3d4,
title = "Binimetinib, a novel MEK1/2 inhibitor, exerts anti-leukemic effects under inactive status of PI3Kinase/Akt pathway",
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.",
keywords = "Akt phosphorylation, G arrest, Myelodysplastic syndromes (MDS), N-RAS mutation",
author = "Kanae Sakakibara and Takayuki Tsujioka and Kida, {Jun ichiro} and Nami Kurozumi and Takako Nakahara and Suemori, {Shin ichiro} and Akira Kitanaka and Yujiro Arao and Kaoru Tohyama",
year = "2019",
month = "1",
day = "1",
doi = "10.1007/s12185-019-02667-1",
language = "English",
journal = "International Journal of Hematology",
issn = "0925-5710",
publisher = "Springer Japan",

}

TY - JOUR

T1 - Binimetinib, a novel MEK1/2 inhibitor, exerts anti-leukemic effects under inactive status of PI3Kinase/Akt pathway

AU - Sakakibara, Kanae

AU - Tsujioka, Takayuki

AU - Kida, Jun ichiro

AU - Kurozumi, Nami

AU - Nakahara, Takako

AU - Suemori, Shin ichiro

AU - Kitanaka, Akira

AU - Arao, Yujiro

AU - Tohyama, Kaoru

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

KW - Akt phosphorylation

KW - G arrest

KW - Myelodysplastic syndromes (MDS)

KW - N-RAS mutation

UR - http://www.scopus.com/inward/record.url?scp=85067656863&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85067656863&partnerID=8YFLogxK

U2 - 10.1007/s12185-019-02667-1

DO - 10.1007/s12185-019-02667-1

M3 - Article

C2 - 31129802

AN - SCOPUS:85067656863

JO - International Journal of Hematology

JF - International Journal of Hematology

SN - 0925-5710

ER -