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.
Highlights
Acute myeloid leukemia (AML) is the second most common form of leukemia in adults, and has a very poor overall survival rate [1, 2]
U937, MV411 and MM6 cells were treated with increasing doses of Tomivosertib for a period of 1 and 4 hours and eukaryotic translation initiation factor 4E (eIF4E) phosphorylation was assessed
Treatment with Tomivosertib abrogated the phosphorylation of eIF4E on serine 209 at a concentration of 0.1 μM, supporting potent inhibition of mitogen-activated protein kinase (MAPK)-interacting kinases 1 and 2 (MNK1/2) activity in AML cells (Figure 1A–1C)
Summary
Acute myeloid leukemia (AML) is the second most common form of leukemia in adults, and has a very poor overall survival rate [1, 2]. Among them are targeted drugs for specific mutations found in AML, such as the FLT3 inhibitors, IDH1/IDH2 inhibitors, pro-apoptotic agents, Hedgehog pathway inhibitors and others [5,6,7]. Even though these therapies have increased at variable degrees the response rates and survival benefit of subgroups of AML patients [8,9,10,11]; the development of resistance towards these novel drugs and subsequent relapse remains one of the major challenges for the treatment of this disease [12]. There continues to be a need for new therapeutic modalities, including approaches targeting negative-feedback signaling pathways that may be activated in response to antileukemic treatments, leading to resistance
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