Journal
NATURE COMMUNICATIONS
Volume 10, Issue -, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-019-13086-5
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Funding
- Herbert Irving Comprehensive Cancer Center (Columbia University) Flow CytometryShared Resource - Cancer Center Support Grant [P30CA013696]
- Dr. John R and Clara M. Fraser Memorial Trust
- Terry Fox Foundation
- Quebec Breast Cancer Foundation
- McGill University
- Columbia University Department of Radiology
- NCATS [UL1TR001873]
- Pancreatic Cancer Action Network [PG009667 - PANCAN 18-35-CHIO]
- V Foundation [PG009685 - VFND V2018-017]
- Columbia University Medical Center (Paul Marks Scholar Award)
- Canadian Institutes of Health Research (CIHR) [FDN-148366]
- Canadian Cancer Research Institute [705096]
- Swedish Research Council
- Swedish Cancer Society
- Stockholm Cancer Society
- Wallenberg Academy Fellow program
- National Institutes of Health (NIH) [R35 GM118173]
- NIH [R24 GM111625]
- Herbert Irving Comprehensive Cancer Center (Columbia University) Small Animal Imaging Shared Resource - Cancer Center Support Grant [P30CA013696]
- Herbert Irving Comprehensive Cancer Center (Columbia University) Molecular Pathology Shared Resource - Cancer Center Support Grant [P30CA013696]
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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.
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