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Targeting DDR2 for Treating Pancreatic Cancer
Chris Tp Do1, Prabhakar Pitta Venkata1, Jack Y Prochnau1
1Greehey Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
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.
Insights
Discoidin Domain Receptor 2 (DDR2) drives pancreatic cancer growth. A new inhibitor, CIDD-8633, effectively blocks tumor growth and enhances chemotherapy, offering a promising new therapeutic strategy for pancreatic ductal adenocarcinoma.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Pancreatic ductal adenocarcinoma (PDAC) presents a significant therapeutic challenge due to its complex tumor microenvironment.
- Limited treatment options exist for PDAC, necessitating novel therapeutic targets and strategies.
Purpose of the Study:
- To identify and characterize novel therapeutic targets for PDAC.
- To evaluate the efficacy of a newly identified DDR2 inhibitor, CIDD-8633, in preclinical models of PDAC.
Main Methods:
- High-throughput screening of small molecule libraries to identify DDR2 inhibitors.
- In vitro assays to assess CIDD-8633's interaction with DDR2 and its downstream signaling.
- In vivo studies using preclinical mouse models to evaluate tumor growth inhibition.
- Combination therapy studies with gemcitabine.
Main Results:
- Discoidin Domain Receptor 2 (DDR2) is highly expressed in PDAC and correlates with poor patient survival.
- CIDD-8633 was identified as a novel small molecule inhibitor targeting DDR2.
- CIDD-8633 demonstrated significant inhibition of PDAC tumor growth in vivo.
- Combination therapy of CIDD-8633 with gemcitabine showed synergistic efficacy.
- CIDD-8633 treatment induced pro-apoptotic genes in PDAC cells.
Conclusions:
- DDR2 is a critical driver of PDAC growth and survival, representing a promising therapeutic target.
- CIDD-8633 is a potent DDR2 inhibitor with significant preclinical efficacy in PDAC.
- CIDD-8633, alone or in combination with gemcitabine, offers a potential new therapeutic strategy for PDAC treatment.
