GPCRs as potential therapeutic targets in pancreatic cancer‐associated fibroblasts (1066.11)

GPCRs as potential therapeutic targets in pancreatic cancer‐associated fibroblasts Shu Zhou 1 , Thalia McCann 1 , Randall French 2 , Andrew M. Lowy 2,3 , Paul A. Insel 1,41 Department of Pharmacology, 2 Moores Cancer Center, 3 Division of Surgical Oncology, Department of Surgery, 4 Department of Medicine, UCSD, La Jolla, California Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense fibrotic stromal matrix, composed of activated fibroblasts/stellate cells, inflammatory cells and other cell types. This unique tumor microenvironment has been increasingly recognized as a key mediator of PDAC progression and drug resistance. Thus, targeting the tumor stroma may be a novel therapeutic approach for PDAC. We hypothesized that G‐protein‐coupled receptors (GPCRs) expressed by pancreatic cancer‐associated fibroblasts (CAFs) may be potential therapeutic targets for PDAC. To begin to test this hypothesis, we used an unbiased GPCRomic array approach to identify and quantify the GPCRs expressed by pancreatic CAFs. We found 125 GPCRs, whose expression was shared in CAFs obtained from the primary tumors of five patients. Among those GPCRs, 35 had at least two‐fold higher expression in the CAFs compared to normal pancreatic fibroblasts and included GPCRs that link to each of the major classes of G proteins. RT‐PCR analysis of the 10 most up‐regulated GPCRs correlated well (r 2 =0.88) with the data from the GPCR array. We conclude that: 1) GPCRomic array analysis can identify and quantify the profile of GPCRs expressed by pancreatic CAFs; 2) the CAF‐expressed profile differs from that of normal pancreatic fibroblasts and 3) GPCRs expressed by CAFs may have functional roles and be novel therapeutic targets for PDAC. Grant Funding Source : Supported by Cancer Therapeutics Training Program