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

• Published in: International journal of hematology Vol. 110; no. 2; pp. 213 - 227
• Main Authors: Sakakibara, Kanae, Tsujioka, Takayuki, Kida, Jun-ichiro, Kurozumi, Nami, Nakahara, Takako, Suemori, Shin-ichiro, Kitanaka, Akira, Arao, Yujiro, Tohyama, Kaoru
• Format: Journal Article
• Language: English
• Published: Tokyo Springer Japan 01.08.2019; Springer Nature B.V
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Aminopyridines - pharmacology; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Benzimidazoles - pharmacology; Biomarkers; Biotechnology; Cell Cycle - drug effects; Cell Line, Tumor; Chemical compounds; DNA, Neoplasm - genetics; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Extracellular signal-regulated kinase; G1 Phase - drug effects; Gene Expression Regulation, Leukemic - drug effects; Gene set enrichment analysis; Genes, ras; Hematology; Humans; Inhibitors; Kinases; Leukemia; Leukemia - genetics; Leukemia - pathology; Levels; Lymphatic leukemia; MAP kinase; MAP Kinase Signaling System - drug effects; Medicine; Medicine & Public Health; Melanoma; Morpholines - pharmacology; Mutation; Myelodysplastic syndromes; Neoplasm Proteins - metabolism; Oncogene Protein p21(ras) - antagonists & inhibitors; Oncology; Original Article; Pharmacology; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; Phosphorylation - drug effects; Protein Kinase Inhibitors - pharmacology; Protein Processing, Post-Translational - drug effects; Proto-Oncogene Proteins c-akt - metabolism; Signal Transduction - drug effects; Tumor cell lines; Myelodysplastic syndromes (MDS); mutation; Akt phosphorylation; arrest; -; G; G1 arrest; N-RAS mutation
• ISSN: 0925-5710; 1865-3774
• DOI: 10.1007/s12185-019-02667-1

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 1 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.