Abstract 5518: Rgs8 and Rgs16 are tumor suppressor genes in mouse pancreatic ductal adenocarcinoma

Abstract

We have identified regulators of G protein signaling (Rgs8 and Rgs16) as a new class of tumor suppressor genes in a mouse model of pancreatic ductal adenocarcinoma (PDA). PDA is the 3rd leading cause of cancer related deaths in the United States. Kras mutations (e.g. KrasG12D) are associated with over 90% of human PDA and are an early event in the multistep process leading to PDA. Kras can be activated by protein kinase and G-Protein Coupled Receptor (GPCR) 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 associated with PDA in humans. We found Rgs8 and Rgs16 are in vivo reporters of Kras activity in pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasm (IPMN), and PDA progression (DMM 8, 2015). Rgs8 and Rgs16 are expressed in PanIN and IPMN, precursors of PDA, in KC mice (LSL-KrasG12D; p48::Cre). To test if Rgs8-16 function as tumor suppressor genes, we crossed the Rgs8-16 double knockout into KC (termed KCR8-16) mice. Compared to KC, PDA initiates earlier, is more aggressive, and KCR8-16 mice die earlier. Our study suggests that Rgs8 and Rgs16 control Kras-dependent PDA initiation and progression. Note: This abstract was not presented at the meeting. Citation Format: Shreoshi Pal Choudhuri, Yalda Zolghadri, Luke Mascarenhas, Ozhan Ocal, Thomas Wilkie. Rgs8 and Rgs16 are tumor suppressor genes in mouse pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5518. doi:10.1158/1538-7445.AM2017-5518