Inhibitory effects of Tomivosertib in acute myeloid leukemia

// Milagros Suarez 1 , Gavin T. Blyth 1 , Alain A. Mina 1 , 2 , Ewa M. Kosciuczuk 1 , 2 , 3 , Blazej Dolniak 1 , Shira Dinner 1 , 2 , Jessica K. Altman 1 , 2 , Elizabeth A. Eklund 1 , 2 , 3 , Diana Saleiro 1 , 2 , Elspeth M. Beauchamp 1 , 2 , 3 and Leonidas C. Platanias 1 , 2 , 3 1 Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA 2 Division of Hematology/Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA 3 Division of Hematology-Oncology, Department of Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, IL, USA Correspondence to: Leonidas C. Platanias, email: l-platanias@northwestern.edu Keywords: MNK; Tomivosertib; acute myeloid leukemia; eIF4E Received: February 23, 2021 Accepted: April 19, 2021 Published: May 11, 2021 Copyright: © 2021 Suarez et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT The MAPK-interacting kinases 1 and 2 (MNK1/2) have generated increasing interest as therapeutic targets for acute myeloid leukemia (AML). We evaluated the therapeutic potential of the highly-selective MNK1/2 inhibitor Tomivosertib on AML cells. Tomivosertib was highly effective at blocking eIF4E phosphorylation on serine 209 in AML cells. Such inhibitory effects correlated with dose-dependent suppression of cellular viability and leukemic progenitor colony formation. Moreover, combination of Tomivosertib and Venetoclax resulted in synergistic anti-leukemic responses in AML cell lines. Mass spectrometry studies identified novel putative MNK1/2 interactors, while in parallel studies we demonstrated that MNK2 - RAPTOR - mTOR complexes are not disrupted by Tomivosertib. Overall, these findings demonstrate that Tomivosertib exhibits potent anti-leukemic properties on AML cells and support the development of clinical translational efforts involving the use of this drug, alone or in combination with other therapies for the treatment of AML.