Molecular Cancer Therapeutics: Targeting DDR2 for Treating Pancreatic Cancer (Rao Lab & Chen)

Chris TP. Do
Prabhakar Pitta Venkata
Jack Y. Prochnau
Deepika Singh
Santosh Timilsina
Panneerdoss Subbarayalu
Daisy Medina
Shahad Abdulsahib
Saif Nirzhor
Sajid Khan
Guiming Li
Srikanth R. Polusani
Daohong Zhou
Pei Wang
Yidong Chen
Ratna K. Vadlamudi
Matthew J. Hart
Radhika Amaradhi
Stanton F. McHardy
Manjeet K. Rao

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with limited effective treatments, partly due to its complex tumor microenvironment. Herein, 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 of PDAC patients. 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 in a synergistic manner. 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, providing new avenues for treating PDAC.

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