Abstract A066: 5z-7-oxozeaenol as an epithelial mesenchymal transition plasticity inhibitor in PDAC

Abstract

Abstract Transcriptional profiling has defined PDAC into distinct classical epithelial (E) or quasi-mesenchymal (QM) subtypes, and these subtypes exist on a continuum of interconverting cell states. This epithelial to mesenchymal transition (EMT) plasticity is thought to be important for the metastatic dissemination and intrinsic resistance to chemotherapy. Our prior work identified TAK1 as an important driver of EMT in mouse circulating tumor cells, and we had identified a compound (5z)-7-oxozeaenol (Oxo) as a small molecule inhibitor of TAK1. Here, we have expanded upon this prior work by evaluating Oxo in 3 human patient derived PDAC cell lines as an EMT plasticity inhibitor. Treatment with Oxo induced a shift of all PDAC cell lines towards an E phenotype in both E and QM PDAC cell lines using RNA-seq and quantitative RNA in situ hybridization. This was associated with increased FFX sensitivity, loss of migratory abilities of all cell lines by Boyden chamber, and decreased invasion in matrigel. Interestingly, genetic TAK1 knockout via CRISPR/Cas9 in these PDAC cell lines showed different effects from Oxo. We found that TAK1 knockout decreased E PDAC cell line migratory behavior and increased FFX sensitivity, but QM PDAC cell lines were not affected by TAK1 knockout. This suggests that QM PDAC cell lines have additional signaling cascades that compensate for TAK1 loss and that Oxo effects across PDAC cell lines are not solely TAK1 dependent. Using phospho-proteomics, in FFX treated PDAC cell lines, we have identified potential candidate pathways in RNA splicing and viral processes that may be additional processes affected by Oxo that merits further investigation. Altogether, we have identified Oxo as a potential broad EMT plasticity inhibitor across PDAC subtypes, and there is a potential role of selective TAK1 inhibitors for E PDAC tumors. Citation Format: Eunae You, Ildiko Phillips E. Phillips, Richard Y. Ebright, Niyati Desai, Michael J. Raabe, Evan R. Lang, Linda T. Nieman, Soroush Hajizadeh, Johannes Kreuzer, Wilhelm Haas, David T. Ting. 5z-7-oxozeaenol as an epithelial mesenchymal transition plasticity inhibitor in PDAC [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A066.