Dual targeting of eIF4E by blocking MNK and mTOR pathways in leukemia

Abstract

Dysregulation of mRNA translation leads to aberrant activation of cellular pathways that promote expansion and survival of leukemic clones. A key element of the initiation translation complex is eIF4E (eukaryotic translation initiation factor 4E). The mitogen-activated protein kinase (MAPK) and mammalian target of rapamycin (mTOR) pathways play important roles in the regulation of eIF4E expression and downstream functional outcomes. Mitogen-activated protein kinase interacting protein kinases (Mnks) control translation by phosphorylation of eIF4E, whereas the mTOR kinase phosphorylates/de-activates the eIF4E inhibitor, 4E-BP1, to release translational repression. Both pathways are often abnormally activated in leukemia cells and promote cell survival events by controlling expression of oncogenic proteins. Targeting these pathways may provide approaches to avoid aberrant proliferation and neoplastic transformation.

MNK1/2 inhibition limits oncogenicity and metastasis of KIT-mutant melanoma

“…Our study, and the work of others (38,39,48,49), strongly support the preclinical development of MNK1/2 inhibitors for the treatment of patients with melanoma, and potentially other malignancies harboring KIT aberrations.…”

Merestinib blocks Mnk kinase activity in acute myeloid leukemia progenitors and exhibits antileukemic effects in vitro and in vivo

“…25 Of the FLT3 mutations, the ITD in AML patients is associated with poor prognosis compared with patients with FLT3 wild-type gene. [25][26][27] The function of eIF4E can be controlled by 2 major pathways that play a critical role in leukemogeniesis, the MAPK and mammalian target of rapamycin pathways, 28 which can be activated downstream of FLT3 receptor. 29,30 Our work demonstrates that inhibition of eIF4E results in antileukemic responses in both FLT3-mutated cell lines and FLT3 WT AML patientderived cells.…”

The Novel Mnk1/2 Degrader VNLG-152 Potently Inhibits TNBC Tumor Growth and Metastasis

“…Furthermore, it is also possible that the ability of our Mnk1/2 degraders to effectively and simultaneously inhibit both Mnk-eIF4E and mTORC1 pathways (Figure 7) may also contribute to their remarkable antitumor and anti-metastasis efficacies in vitro and in vivo. Indeed, recent review articles highlight the significance dual abrogation of Mnk1/2 and mTORC1 as a novel therapeutic approach for the treatment of aggressive cancers (Kosciuczuk et al, 2017;Lineham et al, 2017).…”