eIF4A supports an oncogenic translation program in pancreatic ductal adenocarcinoma

Karina Chan, Francis Robert, Christian Oertlin, Dana Kapeller-Libermann, Daina Avizonis, Johana Gutierrez, Abram Handly-Santana, Mikhail Doubrovin, Julia Park, Christina Schoepfer, Brandon Silva, Melissa Yao, Faith Gorton, Junwei Shi, Craig J. Thomas, Lauren E. Brown, John A. Porco, Michael Pollak, Ola Larsson (), Jerry Pelletier () and Iok In Christine Chio ()
Additional contact information
Karina Chan: Columbia University Medical Center
Francis Robert: McGill University
Christian Oertlin: Karolinska Institute
Dana Kapeller-Libermann: Columbia University Medical Center
Daina Avizonis: McGill University
Johana Gutierrez: Columbia University Medical Center
Abram Handly-Santana: Columbia University Medical Center
Mikhail Doubrovin: Columbia University Medical Center
Julia Park: Cold Spring Harbor Laboratory
Christina Schoepfer: Cold Spring Harbor Laboratory
Brandon Silva: Cold Spring Harbor Laboratory
Melissa Yao: Cold Spring Harbor Laboratory
Faith Gorton: Cold Spring Harbor Laboratory
Junwei Shi: University of Pennsylvania
Craig J. Thomas: National Cancer Institute
Lauren E. Brown: Boston University
John A. Porco: Boston University
Michael Pollak: McGill University
Ola Larsson: Karolinska Institute
Jerry Pelletier: McGill University
Iok In Christine Chio: Columbia University Medical Center

Nature Communications, 2019, vol. 10, issue 1, 1-16

Abstract: Abstract Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy with limited treatment options. Although metabolic reprogramming is a hallmark of many cancers, including PDA, previous attempts to target metabolic changes therapeutically have been stymied by drug toxicity and tumour cell plasticity. Here, we show that PDA cells engage an eIF4F-dependent translation program that supports redox and central carbon metabolism. Inhibition of the eIF4F subunit, eIF4A, using the synthetic rocaglate CR-1-31-B (CR-31) reduced the viability of PDA organoids relative to their normal counterparts. In vivo, CR-31 suppresses tumour growth and extends survival of genetically-engineered murine models of PDA. Surprisingly, inhibition of eIF4A also induces glutamine reductive carboxylation. As a consequence, combined targeting of eIF4A and glutaminase activity more effectively inhibits PDA cell growth both in vitro and in vivo. Overall, our work demonstrates the importance of eIF4A in translational control of pancreatic tumour metabolism and as a therapeutic target against PDA.

Date: 2019
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DOI: 10.1038/s41467-019-13086-5

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