Abstract 5525: Rgs8 and Rgs16 protect against pancreatitis and PDA progression

Abstract

Pancreatic ductal adenocarcinoma (PDA) has the highest death rate among major cancers, and new treatments are desperately needed. The mice we developed in this study, KCR8-16, are an excellent mouse model for identification, characterization, and in vivo validation of novel PDA therapeutics. Kras oncogenic mutations (e.g., KrasG12D) are found in over 90% of human PDA. Kras can be activated by protein kinase and G-protein coupled receptor (GPCR) signaling. Regulator of G-protein signaling (Rgs) proteins regulate GPCR signaling by accelerating the GTPase activity of Gq- and Gi class alpha subunits. Activating alleles of Gq that are resistant to Rgs inhibition are found in benign precursors of PDA in humans. We previously reported that Rgs8 and Rgs16 are in vivo reporters of Kras activity in pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasm (IPMN), and PDA progression in KIC;Rgs16::GFP mice (p48::Cre/+; KrasG12D/+; Cdkn2af/f; Rgs16GFP ) (DMM 8, 2015). To identify the role of Rgs 8 and 16 in PDA, we crossed the Rgs8-16 double knockout into pancreas-specific KrasG12D (KC) mutant mice (termed KCR8-16). We found that deletion of Rgs8 and Rgs16 in KC accelerated PDA progression. Additional pancreatic stress evoked by caerulein treatment caused immediate and pancreas-wide progression to PDA in KCR8-16 mice. Our study suggests that Rgs8 and Rgs16 act as tumor-suppressor genes in PDA initiation and progression. Moreover, KCR8-16 and KIC;Rgs16::GFP mice can be used as an excellent model for identification and rapid in vivo validation of PDA therapeutics. Citation Format: Shreoshi Pal Choudhuri, Yalda Zolghadri, Luke Mascarenhas, Thomas Wilkie. Rgs8 and Rgs16 protect against pancreatitis and PDA progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5525.