Targeting DDR2 for Treating Pancreatic Cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with limited effective treatments, partly because of its complex tumor microenvironment. In this study, we report discoidin domain receptor 2 (DDR2), a receptor tyrosine kinase, as a critical protein that promotes PDAC growth and survival. Our results reveal that DDR2 is highly expressed and its expression correlates with the worst survival outcome in patients with PDAC. Using an unbiased high-throughput screen of small-molecule inhibitor libraries, we identified CIDD-8633, a novel inhibitor targeting DDR2. Our study suggests that CIDD-8633 interacts with DDR2 and inhibits DDR2-associated signaling. Importantly, in vivo studies demonstrate that CIDD-8633 effectively blocks PDAC tumor growth in preclinical mouse models. Additionally, combining CIDD-8633 with gemcitabine enhanced its efficacy synergistically. Mechanistically, CIDD-8633 treatment induces pro-apoptotic genes in PDAC cells. These findings position DDR2 as a promising therapeutic target and CIDD-8633 as a potential DDR2 inhibitor, offering new avenues for the treatment of PDAC.