MRNA translation is a therapeutic vulnerability necessary for bladder epithelial transformation.

Sujata Jana,Kevin R Webster,Nahum Sonenberg,Gary G Chiang,Rucha Deo,Andrew C Hsieh,Jonathan L Wright,Hung-Ming Lam,Yuzhen Liu,Rowan P Hough,Jessie L Horn

doi:10.1172/jci.insight.144920

Abstract

Using genetically engineered mouse models, this work demonstrates that protein synthesis is essential for efficient urothelial cancer formation and growth but dispensable for bladder homeostasis. Through a candidate gene analysis for translation regulators implicated in this dependency, we discovered that phosphorylation of the translation initiation factor eIF4E at serine 209 is increased in both murine and human bladder cancer, and this phosphorylation corresponds with an increase in de novo protein synthesis. Employing an eIF4E serine 209 to alanine knock-in mutant mouse model, we show that this single posttranslational modification is critical for bladder cancer initiation and progression, despite having no impact on normal bladder tissue maintenance. Using murine and human models of advanced bladder cancer, we demonstrate that only tumors with high levels of eIF4E phosphorylation are therapeutically vulnerable to eFT508, the first clinical-grade inhibitor of MNK1 and MNK2, the upstream kinases of eIF4E. Our results show that phospho-eIF4E plays an important role in bladder cancer pathogenesis, and targeting its upstream kinases could be an effective therapeutic option for bladder cancer patients with high levels of eIF4E phosphorylation.

Highlights

Bladder cancer is predicted to have afflicted 81,400 individuals within the United States in 2020
Through a candidate gene analysis for translation regulators implicated in this dependency, we discovered that phosphorylation of the translation initiation factor eukaryotic translation initiation factor 4E (eIF4E) at serine 209 is increased in both murine and human bladder cancer, and this phosphorylation corresponds with an increase in de novo protein synthesis
Using murine and human models of advanced bladder cancer, we demonstrate that only tumors with high levels of eIF4E phosphorylation are therapeutically vulnerable to eFT508, the first clinical-grade inhibitor of MAPK interacting serine/threonine kinase 1 (MNK1) and MNK2, the upstream kinases of eIF4E

Summary

Introduction

Bladder cancer is predicted to have afflicted 81,400 individuals within the United States in 2020. Protein synthesis is a fundamental molecular process that is critical for cancer initiation and progression [9,10,11,12,13] It is unknown whether intact protein synthesis is necessary for normal bladder development and maintenance or the natural history of bladder cancer initiation and progression. These are critical questions because precisely targeting the translation apparatus is becoming increasingly possible through the development of targeted therapeutics with physiologic efficacy in patients [14,15,16]. As such, understanding the protein synthesis requirements of the normal bladder and how it is perturbed in urothelial cancers represents a potential new treatment paradigm

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Results

Conclusion