Targeting Mnks for Cancer Therapy

Jinqiang Hou,Christopher Proud,Shudong Wang,Frankie Lam

doi:10.18632/oncotarget.453

Jinqiang Hou, Christopher Proud + Show 2 more

Open Access

https://doi.org/10.18632/oncotarget.453

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Abstract

Deregulation of protein synthesis is a common event in human cancer and a key player in translational control is eIF4E. Elevated expression levels of eIF4E promote cancer development and progression. Recent findings suggest that eIF4E activity is a key determinant of the PI3K/Akt/mTOR and Ras/Raf/MEK/ERK mediated tumorigenic activity and targeting eIF4E should have a major impact on these pathways in human cancer. The function of eIF4E is modulated through phosphorylation of a conserved serine (Ser209) by Mnk1 and Mnk2 downstream of ERK. While the phosphorylation event is necessary for oncogenic transformation, it seems to be dispensable for normal development. Hence, pharmacologic Mnk inhibitors may provide non-toxic and effective anti-cancer strategy. Strong circumstantial evidence indicates that Mnk inhibition presents attractive therapeutic potential, but the lack of selective Mnk inhibitors has so far confounded pharmacological target validation and clinical development.

Highlights

Mechanism-based targeted cancer therapy represents the remarkable progress of the decades’ research into mechanisms of cancer pathogenesis
Given the importance of the PI3K/Akt/mTOR pathway in regulating mRNA translation of genes that encode for pro-oncogenic proteins and activated mTOR complex1 (mTORC1) signalling in a high proportion of cancers, these kinases have been actively pursued as oncology drug targets [43, 44]
The study failed to reveal any obvious phenotype in Mnk knock-in mice; cells derived from these mice are resistant to Ras-activated oncogenic transformation

Summary

INTRODUCTION

Mechanism-based targeted cancer therapy represents the remarkable progress of the decades’ research into mechanisms of cancer pathogenesis. MTORC1 achieves this by phosphorylation and inactivation of 4E-BPs and the subsequent dissociation of 4E-BPs from eIF4E (Figure 2) This enables eIF4E to interact with the scaffold protein eIF4G permitting assembly of the eIF4F complex for the translation of structured mRNAs [34, 40, 41]. Given the importance of the PI3K/Akt/mTOR pathway in regulating mRNA translation of genes that encode for pro-oncogenic proteins and activated mTORC1 signalling in a high proportion of cancers, these kinases have been actively pursued as oncology drug targets [43, 44]. Mouse embryonic fibroblasts isolated from eIF4E Ser209A mice lacked eIF4E phosphorylation and

F NH2 HN

DESIGN OF SELECTIVE MNK INHIBITORS

Findings

CONCLUSIONS