Abstract
Abstract New and effective therapeutics are urgently needed for the treatment of pancreatic ductal adenocarcinoma (PDAC). The eIF4A/DDX2 RNA helicase drives translation of mRNAs with highly structured 5′UTRs. The natural compound silvestrol and synthetic analogues are potent and selective inhibitors of eIF4A1/2 that show promising activity in models of hematologic malignancies. Here, we show silvestrol analogues have nanomolar activity against PDAC cell lines and organoids in vitro. Moreover, we see single-agent activity in the KRAS/p53 mouse PDAC model and also against PDAC xenograft and primary, patient-derived PDAC tumors. These therapeutic effects occur at nontoxic dose levels. Transcriptome-wide ribosome profiling, analyses of protein and gene expression, and translation reporter studies reveal that KRAS and the RAS signaling network is co-regulated by translation in an eIF4A dependent manner. eIF4A inhibitors block an oncogenic translation program in PDAC cells that includes G-quadruplex containing mRNAs such as KRAS, MYC, YAP1, MET, SMAD3, TGFβ and other components of the RAS signaling network. Together, our data indicate that pharmacologic inhibition of eIF4A disrupts oncoproteins production and shows efficacy across several PDAC models. Citation Format: Kamini Singh, Jianan Lin, Nicolas Lecomte, Prathibha Mohan, Askan Gokce, Viraj Sanghvi, Grbovic-Huezo Olivera, Man Jiang, Antonija Burčul, Stefan Stark, Agnes Viale, Paul B. Romesser, Elisa Destanchia, Rachel Bagni, Gunnar Rätsch, Steve D. Leach, Zhengqing Ouyang, Hans-Guido Wendel. KRAS and RAS signaling network is co-regulated and can be therapeutically blocked by targeting eIF4A dependent translation program [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 B44.