Abstract B17: BET inhibitors block pancreatic stellate cell collagen production and attenuate fibrosis in vivo

Abstract

Abstract The fibrotic reaction, which can account for over 70% of the tumor mass, is a characteristic feature of the majority of human pancreatic ductal adenocarcinoma (PDAC) tumors. It is associated with proliferation of pancreatic stellate cells (PSCs), which are key regulators of collagen production and fibrosis in vivo. In this report we show that bromodomain-containing protein 4 (BRD4), a member of bromodomain and extraterminal (BET) family of proteins, is expressed in activated PSCs in human PDAC tumors. We also show that BET inhibitors and specific targeting of BRD4, in contrast to targeting of BRD2 and BRD3, decrease collagen production by primary PSCs isolated from human PDAC tumors. While BET inhibitors do not induce apoptosis of primary PSCs or affect α-SMA expression, BET inhibitors disrupt α-SMA filament organization in stellate cells. Additionally, BET inhibitors attenuate stellate cell activation, fibrosis and collagen production in vivo in a Kras mouse model of pancreatic tumorigenesis. Our results demonstrate that BET inhibitors regulate fibrosis partly by modulating PSC activation and function. Citation Format: Krishan Kumar, Brian DeCant, Hattaway Z. Hattaway, Paul J. Grippo, David J. Bentrem, Kazumi Ebine, Hidayatullah G. Munshi.{Authors}. BET inhibitors block pancreatic stellate cell collagen production and attenuate fibrosis in vivo. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr B17.