EIF4A supports an oncogenic translation program in pancreatic ductal adenocarcinoma

Karina Chan,Mikhail Doubrovin,Ola Larsson,Dana Kapeller-Libermann,Jerry Pelletier,Julia Park,Faith Gorton,Melissa A Yao ,Abram Handly-Santana,Johana Gutierrez,John A Porco,Junwei Shi,Christian Oertlin,Françis Robert ,Brandon Da Silva,Daina Avizonis,Christina Schoepfer,Lauren E Brown,Michael Pollak,Craig J Thomas,Iok In Christine Chio

doi:10.1038/s41467-019-13086-5

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.

Highlights

Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy with limited treatment options
It is widely acknowledged that a rate-limiting step of cap-dependent translation is the assembly of an active eukaryotic initiation factor 4F (eIF4F) complex[7], high levels of which correlate with poor prognosis and drug resistance in various cancers7,9. eIF4F is a heterotrimeric complex consisting of the cap-binding protein eIF4E, the large scaffolding protein eIF4G, and the DEAD-box RNA helicase eIF4A10
When N and KrasG12D;p53R172Hbearing tumour (KP) organoids were treated with CR-31 for 1 h, we found that N organoids were minimally affected (Fig. 1a), while a striking dose-dependent decrease in nascent protein synthesis was observed in KP organoids as measured by either [35S]-methionine (Supplementary Fig. 1e) or OP-puro (Fig. 1a) incorporation

Summary

Introduction

Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy with limited treatment options. As a consequence, combined targeting of eIF4A and glutaminase activity more effectively inhibits PDA cell growth both in vitro and in vivo. Our work demonstrates the importance of eIF4A in translational control of pancreatic tumour metabolism and as a therapeutic target against PDA. Pancreatic ductal adenocarcinoma (PDA), a highly aggressive malignancy with limited treatment options, is the third leading cause of cancer death in the United States[1]. Using a threedimensional organoid culture system that allows direct comparison between primary tumour cells and their normal, proliferating counterparts[5], we previously showed that PDA is dependent on a KRAS-mediated increase in protein synthesis[6]. It is widely acknowledged that a rate-limiting step of cap-dependent translation is the assembly of an active eIF4F complex[7], high levels of which correlate with poor prognosis and drug resistance in various cancers. The eIF4A helicase is required to unwind cap-proximal secondary structures within the mRNA 5′-UTR during scanning as a prelude to its association with the 43S preinitiation complex, in an ATPdependent fashion[11]

Methods

Results

Conclusion