36P - Molecular assessment of clinical antitumour therapeutics utilising established pancreatic ductal adenocarcinoma patient-derived models

Background

Our proteogenomic analysis using pancreatic ductal adenocarcinoma (PDAC) tissues provides significantly mutated genes/biomarkers, cell signaling pathways and cell types as potential therapeutic targets to improve stratification of PDAC patients (Nat. Can., 2023). The current study aimed to evaluate clinical chemotherapeutics to validate targeting molecules and signaling pathways based on previous results, using patient-derived primary cells and tumor organoids.

Methods

The sensitivity on drugs was also evaluated on established primary PDAC cells and tumor organoids. To explore the mechanistic molecular changes for the development of drug resistance, we established resistant-cells on gemcitabine combined with radiation through long term treatment of the combination and selection procedure. Signaling pathways, EMT and cancer were explored at protein as well as RNA levels, and metabolomics were performed

Results

PDAC cells and organoids showed growth inhibition when treated with inhibitors against RhoA phosphorylation, HIF1A, or gemcitabine combined with radiation, respectively. Each chemotherapeutics showed reduced tumor growth through cell cycle arrest, apoptosis or autophagy. Biochemical analyses showed that drug-treated cells showed reduced expressions of phosphorylated ERK, phosphorylated Akt, or phosphorylated RhoA. HIF1A together with HK2 genes was overexpressed in resistant cells. Metabolomics showed differential glycolysis patterns among parental and resistant primary PDAC cells.

Conclusions

The results suggest that the targeting molecules associated with squamous PDAC malignancy discovered in our previous study would provide significant therapeutic advantage. Additionally, hypoxic tumor microenvironment (TME) plays a critical role for chemotherapeutics sensitivity, according to the metabolomics analysis. Importantly, the study implicates the critical role of patient-derived models, especially tumor organoids, for precise evaluation of drug sensitivity, and to validate functional mechanism of drug resistance on individual PDAC patients.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The author.

Funding

Korea Foundation for the Advancement of Science and Creativity.

Disclosure

All authors have declared no conflicts of interest.