Inhibitory effects of Tomivosertib in acute myeloid leukemia

Milagros Suarez, Gavin T. Blyth, Alain A. Mina, Ewa M. Kosciuczuk, Blazej Dolniak, Shira Dinner, Jessica K. Altman, Elizabeth A. Eklund, Diana Saleiro, Elspeth M. Beauchamp, Leonidas C. Platanias*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)955-966
Number of pages12
JournalOncotarget
Volume12
Issue number10
DOIs
StatePublished - May 11 2021

Keywords

  • Acute myeloid leukemia
  • EIF4E
  • MNK
  • Tomivosertib

ASJC Scopus subject areas

  • Oncology

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