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Updated: Jan 19, 2026
Isolation and Characterization of Patient-derived Pancreatic Ductal Adenocarcinoma Organoid Models
Published on: January 14, 2020
Identification of Resistance Pathways Specific to Malignancy Using Organoid Models of Pancreatic Cancer
Mariano Ponz-Sarvise1,2, Vincenzo Corbo1,2, Hervé Tiriac1,2
1Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.
Purpose:
KRAS is mutated in the majority of pancreatic ductal adenocarcinoma. MAPK and PI3K-AKT are primary KRAS effector pathways, but combined MAPK and PI3K inhibition has not been demonstrated to be clinically effective to date. We explore the resistance mechanisms uniquely employed by malignant cells.
Experimental Design:
We evaluated the expression and activation of receptor tyrosine kinases in response to combined MEK and AKT inhibition in KPC mice and pancreatic ductal organoids. In addition, we sought to determine the therapeutic efficacy of targeting resistance pathways induced by MEK and AKT inhibition in order to identify malignant-specific vulnerabilities.
Results:
Combined MEK and AKT inhibition modestly extended the survival of KPC mice and increased Egfr and ErbB2 phosphorylation levels. Tumor organoids, but not their normal counterparts, exhibited elevated phosphorylation of ERBB2 and ERBB3 after MEK and AKT blockade. A pan-ERBB inhibitor synergized with MEK and AKT blockade in human PDA organoids, whereas this was not observed for the EGFR inhibitor erlotinib. Combined MEK and ERBB inhibitor treatment of human organoid orthotopic xenografts was sufficient to cause tumor regression in short-term intervention studies.
Conclusions:
Analyses of normal and tumor pancreatic organoids revealed the importance of ERBB activation during MEK and AKT blockade primarily in the malignant cultures. The lack of ERBB hyperactivation in normal organoids suggests a larger therapeutic index. In our models, pan-ERBB inhibition was synergistic with dual inhibition of MEK and AKT, and the combination of a pan-ERBB inhibitor with MEK antagonists showed the highest activity both in vitro and in vivo.
Insights
Targeting resistance pathways in pancreatic cancer by combining MEK and AKT inhibitors with pan-ERBB inhibitors shows promise. This approach exploits malignant-specific vulnerabilities for improved therapeutic outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- KRAS mutations are prevalent in pancreatic ductal adenocarcinoma, activating MAPK and PI3K-AKT pathways.
- Combined inhibition of MAPK (MEK) and PI3K-AKT pathways has shown limited clinical efficacy.
- Understanding resistance mechanisms is crucial for developing effective pancreatic cancer treatments.
Purpose of the Study:
- To explore resistance mechanisms in pancreatic ductal adenocarcinoma cells treated with combined MEK and AKT inhibition.
- To evaluate the therapeutic efficacy of targeting resistance pathways induced by MEK and AKT inhibition.
- To identify malignant-specific vulnerabilities in pancreatic cancer.
Main Methods:
- Assessing receptor tyrosine kinase expression and activation in KPC mice and pancreatic ductal organoids.
- Evaluating combined MEK and AKT inhibition efficacy.
- Testing synergistic effects of pan-ERBB inhibitors with MEK and AKT blockade in organoids and xenografts.
Main Results:
- Combined MEK and AKT inhibition showed modest survival benefits in KPC mice and increased EGFR/ErbB2 phosphorylation.
- Malignant organoids, unlike normal ones, displayed elevated ERBB2/ERBB3 phosphorylation after MEK/AKT blockade.
- A pan-ERBB inhibitor synergized with MEK/AKT blockade in human pancreatic ductal adenocarcinoma organoids, leading to tumor regression in xenografts.
Conclusions:
- ERBB activation is critical in malignant pancreatic organoids under MEK/AKT blockade, suggesting a therapeutic window.
- Pan-ERBB inhibition combined with MEK and AKT blockade demonstrates synergistic activity.
- The combination of pan-ERBB and MEK inhibitors exhibits significant anti-tumor activity both in vitro and in vivo.
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