Targeting cholecystokinin‐2 receptor for pancreatic cancer chemoprevention

Gastrin signaling mediated through cholecystokinin‐2 receptor (CCK2R) and its downstream molecules is altered in pancreatic cancer. CCK2R antagonists, YF476 (netazepide) and JNJ‐26070109, were tested systematically for their effect on pancreatic intraepithelial neoplasia (PanIN) progression to pancreatic ductal adenocarcinoma (PDAC) in KrasG12D mice. After dose selection using wild‐type mice, six‐week‐old p48Cre/+‐LSL‐KrasG12D (22‐24 per group) genetically engineered mice (GEM) were fed AIN‐76A diets containing 0, 250, or 500 ppm JNJ‐26070109 or YF‐476 for 38 weeks. At termination, pancreata were collected, weighed, and evaluated for PanINs and PDAC. Results demonstrated that control‐diet‐fed mice showed 69% (males) and 33% (females) incidence of PDAC. Administration of low and high dose JNJ‐26070109 inhibited the incidence of PDAC by 88% and 71% (P .05) in female mice, respectively. Low and high dose YF476 inhibited the incidence of PDAC by 74% (P