Rapid in vivo Screen of Pancreatic Adenocarcinoma Therapeutics

Pancreatic ductal adenocarcinoma (PDA) is the 4 th leading cause of cancer related deaths. Progress towards effective therapy for PDA has been very limited. We are developing a systematic and robust in vivo screen for effective drug combinations. Kras mutations (e.g. Kras G12D ) are found in over 90% of human PDA and occur early in tumor progression. Protein kinase and G‐Protein Coupled Receptor (GPCR) signaling can initiate Ras activation. Regulators of G‐protein Signaling (RGS) proteins are coincidence detectors that can be induced by multiple inputs to feedback regulate GPCR signaling. We previously described Rgs16 expression during embryonic and postnatal pancreas development in pancreatic progenitor and endocrine cells (DMM3, 567). Here, we show that the Rgs16::GFP transgene is a Kras G12D dependent marker of all neoplastic stages in the LSL‐Kras G12D ; Cdkn2a f/f ; p48 Cre (KIC) mice. Rgs16::GFP expression first emerges in ductal Pancreatic Intraepithelial Neoplasia two weeks after birth. The distribution and intensity of Rgs16::GFP increase proportional to tumor burden and extend to acinar cells of distal lobes after occlusion of proximal ducts. RNA‐seq gene expression analysis of primary PDA cell culture shows characteristics of embryonic progenitors of pancreatic ducts and endocrine cells. The receptor tyrosine kinase Axl is a new target for drug development and overexpressed in PDA cells. In a proof‐of‐principle for drug screens, we find PDA weanling mice treated with gemcitabine and Axl inhibitors for 2 weeks have significantly lower quantitative Rgs16::GFP expression and reduced tumor size and occurrence than gemcitabine alone. Rgs16::GFP is hence an in vivo reporter of PDA progression and sensitivity to new chemotherapeutic drug regimens. Supported by NCI CA161624.