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

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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.

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Acknowledgements

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.

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Correspondence to Kaoru Tohyama.

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12185_2019_2667_MOESM1_ESM.jpg

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

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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Sakakibara, K., Tsujioka, T., Kida, Ji. et al. Binimetinib, a novel MEK1/2 inhibitor, exerts anti-leukemic effects under inactive status of PI3Kinase/Akt pathway. Int J Hematol 110, 213–227 (2019). https://doi.org/10.1007/s12185-019-02667-1

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  • DOI: https://doi.org/10.1007/s12185-019-02667-1

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