Abstract
Abstract Pancreatic ductal adenocarcinoma (PDAC) is currently the third leading cause of cancer deaths in the United States and is projected to be in second place by 2030. A key cellular aberration is the activating KRAS mutation (>90%) which in turn leads to stabilizing the MYC oncoprotein and stimulating the growth of PDAC tumors. Dense stroma with elevated levels of hyaluronic acid is another characteristic of PDAC tumors contributing to poor therapeutic response. We describe a novel approach for the treatment of PDAC involving the targeting of thetranslation initiation factor 4A (eIF4A) with a new class of Pateamine A derivatives, DMDA PatA and MZ735.Our data show that nanomolar concentrations of these compounds inhibit cell proliferation and cause G0/G1 arrest in PDAC cell lines. We observed reduction of c-MYC, CyclinD1 and hyaluronic acid synthase HAS3 following treatment with eIF4A targeting compounds. RNA-seq analysis of Miapaca-2 cells treated with MZ735 using the Virtual Inference of Protein-activity by Enriched Regulon analysis (VIPER) algorithm revealed that loss of several MYC gene sets was among the most significantly altered compared to the control cells. We further performed proteomics to better define the consequences of MZ735-induced translation inhibition and observed that several key oncoproteins in PDAC were among the most depleted including MYC, CCND1, and EGFR. Finally, confocal imaging confirmed the reduction of hyaluronic acid in the eIF4A inhibitor-treated PDAC cells. We believe these small molecule compounds represent a new class of anticancer agents that have the potential to address both altered cellular and microenvironment components in PDAC. Citation Format: Maryam Safari, Yu Ri Kim, Prabhjot S. Mundi, Changchun Deng, Susan E. Bates. Targeting translation for the treatment of pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B125. doi:10.1158/1535-7163.TARG-19-B125
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