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. 2016 Jul 21;128(3):410-4.
doi: 10.1182/blood-2016-02-698704. Epub 2016 Jun 15.

Merestinib blocks Mnk kinase activity in acute myeloid leukemia progenitors and exhibits antileukemic effects in vitro and in vivo

Ewa M Kosciuczuk  1 , Diana Saleiro  2 , Barbara Kroczynska  2 , Elspeth M Beauchamp  1 , Frank Eckerdt  2 , Gavin T Blyth  2 , Sameem M Abedin  2 , Francis J Giles  2 , Jessica K Altman  2 , Leonidas C Platanias  1
Affiliations

Merestinib blocks Mnk kinase activity in acute myeloid leukemia progenitors and exhibits antileukemic effects in vitro and in vivo

Ewa M Kosciuczuk et al. Blood. .

Abstract

Mitogen-activated protein kinase interacting protein kinases (Mnks) play important roles in the development and progression of acute myeloid leukemia (AML) by regulating eukaryotic translation initiation factor 4E (eIF4E) activation. Inhibiting Mnk1/2-induced phosphorylation of eIF4E may represent a unique approach for the treatment of AML. We provide evidence for antileukemic effects of merestinib, an orally bioavailable multikinase inhibitor with suppressive effects on Mnk activity. Our studies show that merestinib effectively blocks eIF4E phosphorylation in AML cells and suppresses primitive leukemic progenitors from AML patients in vitro and in an AML xenograft model in vivo. Our findings provide evidence for potent preclinical antileukemic properties of merestinib and support its clinical development for the treatment of patients with AML.

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Figures

Figure 1
Figure 1
Merestinib blocks phosphorylation of eIF4E and suppresses growth of primary leukemic progenitors from AML patients. (A) MV4-11 cells, (B) MM6 cells, and (C) AML patient-derived cells (AML-PT) were incubated with merestinib (LY2801653) at final concentrations of either 0.1 or 1 µM for 1 and 4 hours. Cell lysates were resolved by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunoblotted with an antibody against the phosphorylated form of eIF4E on serine 209. The same blots were stripped and reprobed with an antibody against eIF4E. The immunoblots were also probed for HSP90 as a loading control. (D) MV4-11 and (E) MM6 cells were plated in clonogenic assays in methylcellulose with increasing concentrations of merestinib (LY2801653), as indicated. Data are expressed as percentage of colony formation of control vehicle-treated cells, and bar graphs represent means ± standard error (SE) of 5 independent experiments. (F) Dose-dependent suppression of primary leukemic precursors from AML patients by merestinib in clonogenic assays in methylcellulose. Data are expressed as percentage of colony formation of control vehicle-treated cells. Bar graphs represent means ± SE from 5 independent experiments, using cells from 5 different patients with AML. One-way ANOVA analysis followed by Tukey’s test was used to evaluate statistically significant differences: *P < .05, ****P < .0001.
Figure 2
Figure 2
Antileukemic properties of merestinib in vitro and in vivo. (A) Expression of cell cycle markers in merestinib-treated MV4-11 cells. Cells were treated with or without merestinib (10 nM) for the indicated times. Whole cell lysates were evaluated by western blot analysis with the indicated antibodies. (B-C) MV4-11 cells were incubated for 24 and 48 hours in the presence or absence of merestinib (LY2801653) at the indicated doses. Whole cell lysates were analyzed by western blot with the indicated antibodies. (D-F) MM6 cells were injected subcutaneously into the left flank of nu/nu mice (n = 10). Once tumors reached a measurable size, mice were divided into control (vehicle-Captisol) and merestinib (LY2801653) (12 mg/kg)-treated groups. (D) Mice body weight was recorded throughout the study. (E) Average of tumor volumes treated with vehicle or merestinib. Data are means ± SE of tumor volumes. Mann-Whitney test was used to assess statistically significant differences between the 2 treatment groups (*P < .05, **P < .01, ***P < .001). The arrow symbols indicate that mice were killed when significant morbidity was observed as described in the Study design. (E) Kaplan-Meier survival analysis of control and merestinib-treated mice, P = .0006, using a log-rank (Mantel-Cox) test.
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References

    1. Gilliland DG, Tallman MS. Focus on acute leukemias. Cancer Cell. 2002;1(5):417–420. - PubMed
    1. Dash A, Gilliland DG. Molecular genetics of acute myeloid leukaemia. Best Pract Res Clin Haematol. 2001;14(1):49–64. - PubMed
    1. Carneiro BA, Kaplan JB, Altman JK, Giles FJ, Platanias LC. Targeting mTOR signaling pathways and related negative feedback loops for the treatment of acute myeloid leukemia. Cancer Biol Ther. 2015;16(5):648–656. - PMC - PubMed
    1. Saleiro D, Platanias LC. Intersection of mTOR and STAT signaling in immunity. Trends Immunol. 2015;36(1):21–29. - PMC - PubMed
    1. Beauchamp EM, Platanias LC. The evolution of the TOR pathway and its role in cancer. Oncogene. 2013;32(34):3923–3932. - PubMed

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