Inhibitory effects of Tomivosertib in acute myeloid leukemia

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.

Inhibition MNK‐eIF4E‐β‐catenin preferentially sensitizes gastric cancer to chemotherapy

“…Tomivosertib activity in models of various cancers is associated with potent inhibition of eIF4E phosphorylation at S209 [13,22,24]. In gastric cancer, our mechanism analysis indicates that (1) MNK/ eIF4E/β-catenin is responsible for tomivosertib activity, (2) MNK/eIF4E regulates β-catenin expression and activity, (3) tomivosertib decreases β-catenin level via eIF4E-mediated translation but not CK1-mediated degradation, and (4) p-eIF4E is dispensable for gastric cancer cell viability (Figures 3 and 4).…”

“…As a MNK inhibitor, tomivosertib has been shown to act on cancer cells via suppressing eIF4E [13,22]. Given the importance of eIF4E signaling in gastric cancer [9,10], we investigated if eIF4E is the molecular target of tomivosertib.…”

MNK Proteins as Therapeutic Targets in Leukemia

“… 79 Most recently, our group tested tomivosertib in the same established AML cell lines and also saw a reduction in cell viability and colony formation with the highest potency against MV411, MM6 cells, and KG-1 cells. 9 Through these four studies, we have found that MNK inhibitors ranging from unselective multi-kinase to very MNK specific all have antineoplastic effects in AML models.…”

“… 77 Tomivosertib showed synergistic effects in viability and colony formation reduction with venetoclax, a BCL2 inhibitor approved in CLL and AML in combination with hypomethylating agents or low-dose chemotherapy. 9 Combination targets as well as dual MNK inhibitors are highlighted in Table 3 .…”

“… 7 , 8 Alternatively, more specific MNK inhibitors, such as tomivosertib, are also being explored and have a potential place in combination treatments in efforts to overcome resistance. 9 Many groups are still working to develop potent and selective MNK inhibitors with desirable pharmacokinetic properties, while others are focusing on understanding MNK mechanistic elements. There are only three clinical trials that have been initiated utilizing MNK inhibitors in hematological malignancies, but optimized inhibitors and preclinical evidence of combinatorial benefits of MNK inhibitors could promote further clinical research.…”