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Updated: Jul 7, 2025
Isolation and Characterization of Patient-derived Pancreatic Ductal Adenocarcinoma Organoid Models
Published on: January 14, 2020
A pancreatic cancer organoid platform identifies an inhibitor specific to mutant KRAS
Xiaohua Duan1, Tuo Zhang2, Lingling Feng3
1Department of Surgery, Weill Cornell Medicine, 1300 York Ave., New York, NY 10065, USA; Center for Genomic Health, 1300 York Ave., New York, NY 10065, USA.
Abstract:
KRAS mutations, mainly G12D and G12V, are found in more than 90% of pancreatic ductal adenocarcinoma (PDAC) cases. The success of drugs targeting KRASG12C suggests the potential for drugs specifically targeting these alternative PDAC-associated KRAS mutations. Here, we report a high-throughput drug-screening platform using a series of isogenic murine pancreatic organoids that are wild type (WT) or contain common PDAC driver mutations, representing both classical and basal PDAC phenotypes. We screened over 6,000 compounds and identified perhexiline maleate, which can inhibit the growth and induce cell death of pancreatic organoids carrying the KrasG12D mutation both in vitro and in vivo and primary human PDAC organoids. scRNA-seq analysis suggests that the cholesterol synthesis pathway is upregulated specifically in the KRAS mutant organoids, including the key cholesterol synthesis regulator SREBP2. Perhexiline maleate decreases SREBP2 expression levels and reverses the KRAS mutant-induced upregulation of the cholesterol synthesis pathway.
Insights
Researchers identified perhexiline maleate as a potential drug to treat pancreatic cancer. This compound inhibits growth and induces cell death in pancreatic ductal adenocarcinoma (PDAC) organoids with KRAS mutations.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- KRAS mutations, particularly G12D and G12V, are prevalent in over 90% of pancreatic ductal adenocarcinoma (PDAC) cases.
- Targeting KRAS G12C mutations has shown therapeutic success, highlighting the need for drugs against other common PDAC-associated KRAS mutations.
Purpose of the Study:
- To develop and utilize a high-throughput drug-screening platform for identifying novel therapeutic agents against PDAC.
- To investigate potential drug candidates targeting KRAS G12D and other PDAC-associated mutations.
Main Methods:
- Established a screening platform using isogenic murine pancreatic organoids (wild type and with common PDAC driver mutations).
- Screened over 6,000 compounds to identify inhibitors of KRAS-mutant pancreatic organoids.
- Utilized single-cell RNA sequencing (scRNA-seq) to analyze molecular pathways affected by identified compounds.
Main Results:
- Identified perhexiline maleate as a compound that inhibits growth and induces cell death in Kras G12D-mutant pancreatic organoids (in vitro and in vivo) and human PDAC organoids.
- Discovered that the cholesterol synthesis pathway, including SREBP2, is upregulated in KRAS-mutant organoids.
- Demonstrated that perhexiline maleate downregulates SREBP2 expression and reverses the upregulation of the cholesterol synthesis pathway in KRAS-mutant organoids.
Conclusions:
- Perhexiline maleate shows significant therapeutic potential for KRAS G12D-mutant pancreatic ductal adenocarcinoma.
- Targeting the cholesterol synthesis pathway represents a promising strategy for treating PDAC with specific KRAS mutations.
- The developed screening platform is effective for identifying novel PDAC drug candidates.
