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Updated: Jun 11, 2026
Reprogramming Pancreatic Ductal Adenocarcinoma to Pluripotency
Published on: February 2, 2024
The Protein Phosphatase Inhibitor LB100 Targets the Mesenchymal Lineage of Pancreatic Ductal Adenocarcinoma
Janine Murr1, Carolin Schneider2, Ningjun Duan2
1Medical Clinic and Polyclinic II Klinikum Rechts Der Isar Technical University Munich Munich Germany.
Abstract:
Pancreatic ductal adenocarcinoma (PDAC) remains a therapeutic challenge, and the aggressive basal-like/mesenchymal subtype is particularly refractory to chemotherapy, underscoring the need for novel therapies. Leveraging genetic screens, we identified protein phosphatase 2A (PP2A) catalytic subunit PPP2CA as a target. Pharmacological PP2A inhibition selectively impaired the growth of mesenchymal PDAC cells. To delineate the mechanisms underlying sensitivity to the PP2A inhibitor LB100, we employed a dual-pronged strategy. Functional characterization revealed metabolic reprogramming coupled with endoplasmic reticulum (ER) stress and cell death induction. Genome-wide genetic screens identified key modifiers of LB100 sensitivity, implicating transcriptional regulators, mRNA processing, translation, and metabolism. Based on expression data linking PP2A to splicing and transcriptional regulation, we prioritized these processes for validation. Mesenchymal PDAC cells exhibited enhanced splicing following PP2A inhibition. Notably, we identified enhanced transcriptional elongation upon LB100 treatment, particularly of short genes, driven by cyclin-dependent kinase 9 (CDK9). Our findings support a reciprocal regulatory relationship between PP2A and CDK9 that connects to the activation of ER stress response factors, including activating transcription factor 4 (ATF4). These results establish PP2A as a druggable target in mesenchymal PDAC cells and reveal a role of LB100-induced transcriptional elongation and splicing, providing a mechanistic basis to guide future therapy development.
Insights
Targeting protein phosphatase 2A (PP2A) with LB100 selectively inhibits aggressive pancreatic cancer (PDAC) growth. This novel therapy induces metabolic changes, endoplasmic reticulum stress, and cell death by affecting gene transcription and splicing.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Pancreatic ductal adenocarcinoma (PDAC), especially the mesenchymal subtype, is difficult to treat with chemotherapy.
- There is a critical need for novel therapeutic strategies targeting PDAC.
Purpose of the Study:
- To identify and validate new therapeutic targets in mesenchymal PDAC.
- To elucidate the mechanisms of action for the PP2A inhibitor LB100 in PDAC.
Main Methods:
- Genetic screens were used to identify PPP2CA as a therapeutic target.
- Functional characterization involved metabolic analysis, ER stress assessment, and cell death assays.
- Genome-wide screens identified modifiers of LB100 sensitivity.
- Transcriptional and splicing analyses were performed.
Main Results:
- PP2A inhibition by LB100 selectively impaired mesenchymal PDAC cell growth.
- LB100 treatment induced metabolic reprogramming, ER stress, and cell death.
- LB100 enhanced transcriptional elongation and splicing, particularly in short genes, mediated by CDK9.
- A regulatory loop between PP2A and CDK9, linked to ATF4 and ER stress, was identified.
Conclusions:
- PP2A is a druggable target in mesenchymal PDAC.
- LB100's mechanism involves modulating transcriptional elongation and splicing.
- These findings provide a basis for developing new therapies for refractory PDAC subtypes.
