Targeting the eIF4A dependent translation of KRAS and other oncoproteins in pancreatic cancer

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 hematological 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 xenografts and primary, patient derived PDAC tumors. These therapeutic effects occur at non-toxic dose levels. Transcriptome-wide ribosome profiling, analyses of protein and gene expression, and translation reporter studies reveal that eIF4A inhibitors block an oncogenic translation program in PDAC cells that includes G-quadruplex containing mRNAs such as KRAS, MYC, YAP1, MET, SMAD3, TGFß and others. Together, our data indicate that pharmacological inhibition of eIF4A disrupts oncoprotein production and shows efficacy across several PDAC models. Overall design: We performed ribosome footprinting and RNA sequencing on six samples of PANC1 cells including three untreated samples (DMSO) and three samples that were collected 45 minutes after treatment with CR31B (25 nM). DMSO treated samples are indicated as CT and CR31B treated samples are indicate as S.