Abstract A29: Bicompartmental regulation of disease-related gene networks by histone deacetylase inhibition curbs pancreatic cancer progression

A challenge for effective pancreatic ductal adenocarcinoma (PDAC) therapy is to target the aggressive neoplasm that is shrouded by the dense fibrotic stroma. Epigenetic modulation has the potential to regulate genes or gene networks causing disease phenotypes. Here we show that the HDAC inhibitor entinostat (Ent) provides therapeutic benefits by regulating the gene networks important for PDAC in both the stromal and epithelial compartments. While an HDAC inhibitor is anticipated to broadly open chromatin and activate genes, in stromal pancreatic stellate cells (PSCs), Ent unexpectedly restricts chromatin accessibility on and represses the gene networks essential for PSC activation, leading to proliferation arrest and reduced myofibroblast properties, including lower production of extracellular matrix and inflammatory and protumorigenic cytokines. Furthermore, Ent also attenuates the transcriptional responses of cancer-associated fibroblasts (CAFs) to injury-related cytokines from the tumor microenvironment including TGF-beta and TNF-alpha. In the neoplastic epithelium, Ent induces cytostasis and de novo vulnerability in DNA repair pathways by systematically suppressing cell cycle and DNA repair genes. Notably, the bicompartmental effects of Ent were found to arrest cancer progression, prolong survival, and synergize with DNA damage-inducing agent cisplatin in genetically engineered mouse model (GEMM) of PDAC. Overall, our study not only establishes Ent as a novel therapeutic agent for PDAC but also reveals the mechanisms underlying its benefits. Citation Format: Gaoyang Liang, Nasun Hah, Yu Shi, Morgan L. Truitt, Corina E. Antal, Annette R. Atkins, Cory Fraser, Ester Banayo, Senada Bashi, Yang Dai, Mara Sherman, Christopher Liddle, Ruth T. Yu, Tony Hunter, Haiyong Han, Daniel D. Von Hoff, Michael Downes, Ronald M. Evans. Bicompartmental regulation of disease-related gene networks by histone deacetylase inhibition curbs pancreatic cancer progression [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr A29.