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Oncotarget: Inhibitory effects of Tomivosertib in acute myeloid leukemia


FOR IMMEDIATE RELEASE
2021-05-17

Oncotarget published "Inhibitory effects of Tomivosertib in acute myeloid leukemia" which reported that the authors 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.

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 Oncotarget 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.

These Oncotarget 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

Dr. Leonidas C. Platanias from The Northwestern University as well as The Jesse Brown Veterans Affairs Medical Center said, "Acute myeloid leukemia (AML) is the second most common form of leukemia in adults, and has a very poor overall survival rate."

Therefore, 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.

The pro-neoplastic activity of eIF4E is associated with its phosphorylation/activation by MNK1/2 on serine 209 and correlates with enhanced mRNA translation, as well as nuclear export of mRNAs involved in tumorigenesis and cell cycle control.

Several studies have shown that pharmacological targeting of MNK1/2 results in inhibitory activity against AML cells in pre-clinical models.

Figure 4: LC-MS/MS analysis identifies putative MNK1/2 targets and interactors. (A) FLAG-MNK2 or FLAG-MNK1 was overexpressed in 293T cells. MNK1/2 was immunoprecipitated from 293T cell lysates using anti-FLAG-M2 agarose conjugated beads. An empty vector was used as a negative control. Immunoprecipitated proteins were resolved by SDS-PAGE, and were prepared using standard techniques and then analyzed via LC-MS/MS. A Venn diagram was created depicting the number of proteins that interact with MNK1/2. (B) The results from (A) were annotated using Metascape. The heat map shows the most significant pathways and the overlap between the MNK1 IP and MNK2 IP. (C) FLAG-MNK2 or FLAG-MNK1 was immunoprecipitated as described in (A). Proteins were resolved by SDS-PAGE and immunoblotted with the indicated antibodies. (D) FLAG-MNK2 was overexpressed in 293T cells. Cells were treated with either DMSO (vehicle-control) or Tomivosertib at the indicated doses and time points, lysed and MNK2 was immunoprecipitated with anti-FLAG-M2 agarose conjugated beads. An empty vector (EV) was used as a negative control. Proteins were resolved by SDS-PAGE and immunoblotted with the indicated antibodies. (E) HA-RAPTOR was overexpressed in 293T cells. Cells were treated with either DMSO (vehicle-control) or Tomivosertib at the indicated doses and time points, lysed and RAPTOR was immunoprecipitated with anti-HA Sepharose conjugated beads. An empty vector (EV) was used as negative control. Proteins were resolved by SDS-PAGE and immunoblotted with the indicated antibodies. (C–E) Total cell lysates for each experimental condition were run in parallel with the immunoprecipitated proteins (Input).

As a result, the full therapeutic potential of MNK1/2 inhibition for the treatment of AML has not been fully assessed.

The authors demonstrate that Tomivosertib suppresses eIF4E phosphorylation in AML cells and decreases leukemic cell survival and proliferation.

The Platanias Research Team concluded in their Oncotarget Research Output, "Viewed altogether, these studies indicate that MNK1/2 inhibition would most likely be a successful strategy in only a subset of AML patients. In future studies it will be crucial to ascertain what pathways are responsible for sensitivity to MNK inhibitors. These studies will help to identify potential regulatory programs through which MNK1/2 modulates cell signaling pathways critical for leukemic cell survival and may lead to the development of novel therapeutic interventions for AML."

DOI - https://doi.org/10.18632/oncotarget.27952

Full text - https://www.oncotarget.com/article/27952/text/

Correspondence to - Leonidas C. Platanias - l-platanias@northwestern.edu

Keywords - MNK, Tomivosertib, acute myeloid leukemia, eIF4E

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