Targeting eIF4A-dependent translation of KRAS signaling molecules

Kamini Singh, Jianan Lin, 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 StanchinaAndrew W. Stamford, Peter T. Meinke, Gunnar Rätsch, Steven D. Leach, Zhengqing Ouyang, Hans Guido Wendel

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Pancreatic adenocarcinoma (PDAC) epitomizes a deadly cancer driven by abnormal KRAS signaling. Here, we show that the eIF4A RNA helicase is required for translation of key KRAS signaling molecules and that pharmacological inhibition of eIF4A has singleagent 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 50 untranslated regions, including those with multiple G-quadruplex 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.

Original languageEnglish (US)
Pages (from-to)2002-2014
Number of pages13
JournalCancer Research
Volume81
Issue number8
DOIs
StatePublished - Apr 2021

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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