Abstract IA13: Targeting redox dependencies in pancreatic cancer

Dysregulation of mRNA translation is a common feature of human cancers. As such, therapeutic agents that target components of the protein synthesis apparatus hold promise as anticancer drugs. We previously showed that protein synthesis is upregulated in Kras mutant pancreatic cancer cells in a manner that is redox-dependent (1). By modulating formation of the eIF4F complex, the PI3K/AKT and mTOR signaling pathways act as major regulators of global and mRNA-specific translation. Consistently, we observed that protein synthesis and the viability of pancreatic tumor organoids are selectively decreased by the pan-AKT inhibitor MK2206, an effect that was potentiated by co-treatment with the pro-oxidant BSO1. Treatment of KrasG12D;p53R172H;PdxCre (KPC) mice with this drug combination resulted in suppressed tumor kinetics and modest improvement in survival. Inhibition of AKT/mTOR blunts cap-dependent translation initiation but also perturbs a plethora of other cellular functions. We thus investigated more selective means of targeting the translation machinery that do not entail wholesale ablation of the AKT/mTOR pathway. The RNA helicase eIF4A initiates translation by unwinding highly structured 5′-untranslated regions (UTRs) in mRNAs. Using polysome profiling followed by deep sequencing, we found that the translation of eIF4A-sensitive mRNAs was selectively increased in Kras-mutant tumor versus normal organoids. The rocaglate, CR-13-1b, is a compound that selectively inhibits the eIF4A helicase and displayed high toxicity in Kras mutant tumor organoids, but not in normal organoids. Polysome sequencing revealed that CR131b selectively modulates translational efficiencies in tumor but not normal organoids. Interestingly, this included multiple mRNAs encoding proteins involved in mitochondrial activity and redox homeostasis. As a single agent, CR131b treatment in KPC mice effectively inhibited protein synthesis in vivo, resulting in a significant decrease in tumor kinetics in a short-term study and an improvement in survival in a longitudinal study. Reference 1. Chio II et al. NRF2 promotes tumor maintenance by modulating mRNA translation in pancreatic cancer. Cell 2016;166:963-76, doi:10.1016/j.cell.2016.06.056. Citation Format: Iok In Christine Chio, Christian Oertlin, Francis Robert, Karina Chan, Dana Kapellar Liberm, Abram Santana, Young Park, Ola Larsson, Jerry Pelletier, David Tuveson. Targeting redox dependencies in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr IA13.