Abstract 2702: A novel inhibitor targeting DDR complex to suppress pancreatic cancer growth and progression

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy, with a 5-year survival rate of 12%. The dense extracellular matrix (ECM) and cancer-associated fibroblast (CAF)-driven microenvironment contribute to tumor progression and resistance to current therapies, necessitating the development of novel treatments. This study introduces CIDD-8633, a selective small-molecule inhibitor targeting the Discoidin Domain Receptor (DDR) complex, which plays a crucial role in ECM-mediated signaling and PDAC progression. High-throughput screening identified CIDD-8633 as a potent inhibitor of DDR kinase activity. Functional assays demonstrated that CIDD-8633 significantly reduced PDAC cell proliferation, migration, and colony formation while inducing apoptosis and G1/S cell cycle arrest. RNA sequencing revealed that CIDD-8633 treatment downregulated pathways associated with DNA replication and repair, while upregulating apoptosis-related signaling pathways. In vivo, CIDD-8633 effectively suppressed tumor growth in PDAC xenograft models, reducing tumor volume and proliferation markers. Histopathological analysis showed decreased phosphorylated DDR and downstream RTKs expression, accompanied by enhanced apoptotic signaling. Furthermore, combination therapy with gemcitabine demonstrated synergistic effects, enhancing anti-tumor efficacy by reducing PDAC cell viability and metastatic potential more effectively than either agent alone. These findings position CIDD-8633 as a promising therapeutic candidate for PDAC, capable of targeting the DDR complex to disrupt tumor progression. This study highlights the potential of DDR inhibition as a novel therapeutic approach for overcoming the challenges of this aggressive cancer. Citation Format: Chrid TP Do, Prabhakar P. Venkata, Jack Y. Prochnau, Deepika Singh, Santosh Timilsina, Panneerdoss Subbarayalu, Daisy Medina, Shahad Abdulsahib, Sajeed Khan, Manjeet K. Rao. A novel inhibitor targeting DDR complex to suppress pancreatic cancer growth and progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2702.