Inhibitory effects of Tomivosertib in acute myeloid leukemia
| Autor: | Milagros Suarez, Leonidas C. Platanias, Shira Dinner, Elizabeth A. Eklund, Alain Mina, Ewa M. Kosciuczuk, Jessica K. Altman, Gavin T. Blyth, Elspeth M. Beauchamp, Blazej Dolniak, Diana Saleiro |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Venetoclax Kinase MNK EIF4E Myeloid leukemia acute myeloid leukemia Serine 03 medical and health sciences chemistry.chemical_compound 030104 developmental biology 0302 clinical medicine Oncology chemistry Cell culture 030220 oncology & carcinogenesis hemic and lymphatic diseases eIF4E Cancer research Phosphorylation Tomivosertib PI3K/AKT/mTOR pathway Research Paper |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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