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Published on: December 23, 2022
Matrix stiffness influences drug resistance to gemcitabine analog and AZD 1775 combination in PDAC organoids
Jonathan Barajas1, Zhi Yang1, Edward Agyare2
1Departments of Surgery and Biomedical Engineering, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
Background:
Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal cancers, with limited therapeutic advancements and rapid development of treatment resistance. Fatty acid-conjugated gemcitabine analogs have shown improved antitumor efficacy. This study investigates the effects of gemcitabine conjugated with caprylic acid (Gemcitabine-8C) in combination with AZD 1775, a WEE1 inhibitor, using patient-derived PDAC organoids.
Methods:
Patient-derived PDAC cells (G43, G46) were cultured in a gelatin-based 3D organoid system with tunable stiffness to mimic the tumor microenvironment. Cells were treated with gemcitabine, Gemcitabine-8C, AZD 1775, or their combination. The study assessed treatment efficacy, extracellular matrix influence, morphology, gene expression, and drug resistance mechanisms.
Results:
The combination of AZD 1775 and Gemcitabine-8C significantly enhanced treatment efficacy compared to monotherapies or gemcitabine with AZD 1775. G43 cells were more sensitive to treatment than G46. Increased matrix stiffness correlated with greater drug resistance. Resistant cells exhibited elevated oxidative stress, while sensitive cells showed F-actin structural alterations absent in resistant counterparts.
Conclusions:
AZD 1775 enhances the efficacy of Gemcitabine-8C at non-toxic doses, demonstrating its potential for overcoming PDAC treatment resistance. The cell origin and tumor microenvironment plays a key role in modulating drug response, highlighting the need for microenvironment and individualized-targeted strategies.
Insights
The combination of AZD 1775 and Gemcitabine-8C significantly improves pancreatic cancer treatment. This approach shows promise in overcoming drug resistance by targeting the tumor microenvironment.
Area of Science:
- Oncology
- Cancer Biology
- Drug Discovery
Background:
- Pancreatic ductal adenocarcinoma (PDAC) presents significant therapeutic challenges due to limited advancements and rapid resistance development.
- Fatty acid-conjugated gemcitabine analogs offer potential for enhanced antitumor activity.
- This study explores the combination of Gemcitabine-8C and the WEE1 inhibitor AZD 1775 in PDAC.
Purpose of the Study:
- To evaluate the efficacy of Gemcitabine-8C combined with AZD 1775 in patient-derived PDAC organoids.
- To investigate the influence of the tumor microenvironment, specifically matrix stiffness, on treatment response.
- To elucidate mechanisms of drug resistance in PDAC.
Main Methods:
- Patient-derived PDAC cells (G43, G46) were cultured in 3D organoids with controlled matrix stiffness.
- Organoids were treated with gemcitabine, Gemcitabine-8C, AZD 1775, or their combination.
- Assessment included treatment efficacy, extracellular matrix effects, morphology, gene expression, and resistance mechanisms.
Main Results:
- The combination of AZD 1775 and Gemcitabine-8C demonstrated significantly enhanced efficacy over monotherapies.
- Increased matrix stiffness correlated with heightened drug resistance in PDAC organoids.
- Resistant cells showed elevated oxidative stress, while sensitive cells had distinct F-actin alterations.
Conclusions:
- AZD 1775 potentiates Gemcitabine-8C efficacy at non-toxic doses, offering a strategy to overcome PDAC treatment resistance.
- Cell origin and tumor microenvironment critically modulate drug response, necessitating tailored therapeutic strategies.
- Individualized and microenvironment-targeted approaches are crucial for effective PDAC treatment.
