eIF4A supports an oncogenic translation program in pancreatic ductal adenocarcinoma

• Published in: Nature communications 2019-11, Vol.10 (1), p.5151-16, Article 5151
• Main Authors: Chan, Karina, Robert, Francis, Oertlin, Christian, Kapeller-Libermann, Dana, Avizonis, Daina, Gutierrez, Johana, Handly-Santana, Abram, Doubrovin, Mikhail, Park, Julia, Schoepfer, Christina, Da Silva, Brandon, Yao, Melissa, Gorton, Faith, Shi, Junwei, Thomas, Craig J., Brown, Lauren E., Porco, John A., Pollak, Michael, Larsson, Ola, Pelletier, Jerry, Chio, Iok In Christine
• Format: Article
• Language: English
• Subjects: 13/106; 13/31; 13/51; 13/95; 14/5; 14/63; 38/39; 38/91; 59; 631/154; 631/337; 631/67; 631/80; 64/60; Adenocarcinoma; Animal models; Animals; Biocompatibility; Carboxylation; Carcinogenesis; Carcinoma, Pancreatic Ductal - metabolism; Cell Line, Tumor; Eukaryotic Initiation Factor-4A - antagonists & inhibitors; Eukaryotic Initiation Factor-4A - metabolism; Genetic engineering; Glutaminase; Glutamine; Glutathione - metabolism; Humanities and Social Sciences; Humans; Malignancy; Metabolism; Mice, Inbred C57BL; Molecular Targeted Therapy; multidisciplinary; Organoids; Oxidation-Reduction; Pancreas; Pancreatic cancer; Pancreatic Neoplasms; Pancreatic Neoplasms - metabolism; Protein Biosynthesis; Science; Science (multidisciplinary); Therapeutic applications; Toxicity; Translation; Tumors; Viability
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-13086-5

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. Metabolic reprogramming is a hallmark of pancreatic ductal adenocarcinoma (PDA). Here, the authors show that in PDA cells redox and central carbon metabolism are driven by an eIF4F dependent translation program, and combined targeting of eIF4A and glutaminase can impact PDA proliferation.