Targeting eIF4A Dependent Translation of KRAS Signaling Molecules.

Kamini Singh
Jianan Lin, The Jackson Laboratory
Nicolas Lecomte
Prathibha Mohan
Askan Gokce
Viraj R Sanghvi
Man Jiang
Olivera Grbovic-Huezo
Antonija Burčul
Stefan G Stark
Paul B Romesser
Qing Chang
Jerry P Melchor
Rachel K Beyer
Mark Duggan
Yoshiyuki Fukase
Guangli Yang
Ouathek Ouerfelli
Agnes Viale
Elisa de Stanchina
Andrew W Stamford
Peter T Meinke
Gunnar Rätsch
Steven D Leach
Zhengqing Ouyang, The Jackson Laboratory
Hans-Guido Wendel


Pancreatic adenocarcinoma (PDAC) epitomizes a deadly cancer driven by abnormal KRAS signalling. Here we show that the eIF4A RNA helicase is required for translation of key KRAS signaling molecules and that pharmacological inhibition of eIF4A has single-agent activity against murine and human PDAC models at safe dose levels. EIF4A was uniquely required for the translation of mRNAs with long and highly structured 5'UTRs including those with multiple G-quadruplex (GQ) elements. Computational analyses identified these features in mRNAs encoding KRAS and key downstream molecules. Transcriptome-scale ribosome footprinting accurately identified eIF4A-dependent mRNAs in PDAC including critical KRAS signaling molecules such as PI3K, RALA, RAC2, MET, MYC, and YAP1. These findings contrast with a recent study that relied on an older method, polysome fractionation, and implicated redox-related genes as eIF4A clients. Together, our findings highlight the power of ribosome footprinting in conjunction with deep RNA sequencing in accurately decoding translational control mechanisms and define the therapeutic mechanism of eIF4A inhibitors in PDAC.