Abstract B104: Epigenetic small molecule library screen to discover compounds that inhibit and reverse pancreatic acinar to ductal metaplasia

Abstract Pancreatic ductal adenocarcinoma (PDAC) development is believed to be preluded by the event of acinar to ductal metaplasia (ADM), the transdifferentiation of acinar cells into a duct-like state. It is widely accepted that either acinar or ductal cells bearing mutant Kras drive the development of PDAC. We have previously shown that we can inhibit and reverse ADM in a 3D organoid assay using primary pancreatic tissue from p48Cre/+LSL-KRASG12D/+ mice using the histone deacetylase inhibitor (HDACi), Trichostatin A (Da Silva, 2022). We further employed our 3D organoid model to perform a phenotypic and molecular screening of 144 epigenetic compounds. We identified class I HDACi, FK228, and the histone methyltransferase inhibitor, Chaetocin, as the top hits of reversing ADM without inducing cytotoxicity as assessed by calcein AM staining. Largazole homodomer, a novel HDACi derived from marine cyanobacteria, was also identified as both an inhibitor and reversal agent of ADM. These three compounds demonstrated phenotypic and molecular reversal of duct-like structures back into their acinar state, in addition to relative mRNA upregulation of acinar markers (Amy2a, Cela1, Cpa2) and downregulation of ductal markers (Krt19, Krt7, Sox9). Bulk-RNA sequencing combined with pathway analysis demonstrated pronounced inhibition of cancer signaling pathways during ADM reversal, such as TGFβ1, Vegf, TNF, IL-6, and STAT3. Moreover, RNA sequencing showed significant upregulation and downregulation of acinar and ductal/PDAC markers, respectively. Thus, a novel phenotypic small molecular screen based on organoid morphology was developed to discover compounds that inhibit and reverse pancreatic ADM in a mouse model with mutant Kras. Citation Format: Corey M. Perkins, Kalina R. Atanasova, Ranjala Ratnayake, Jinmai Jiang, Qi-Yin Chen, Thomas D. Schmittgen, Hendrik Luesch. Epigenetic small molecule library screen to discover compounds that inhibit and reverse pancreatic acinar to ductal metaplasia [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B104.