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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.
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 Gemcitabine-8C and AZD 1775 shows promise in overcoming pancreatic cancer resistance. This novel therapeutic strategy, tested in patient-derived organoids, offers new hope for treating this lethal disease.
Area of Science:
- Oncology
- Cancer Biology
- Drug Discovery
Background:
- Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer with poor therapeutic outcomes and rapid resistance development.
- Fatty acid-conjugated gemcitabine analogs offer potential for improved antitumor efficacy.
- Investigating novel therapeutic combinations is crucial for advancing PDAC treatment.
Purpose of the Study:
- To evaluate the efficacy of Gemcitabine-8C, a caprylic acid-conjugated gemcitabine analog, in combination with AZD 1775 (a WEE1 inhibitor).
- To assess the impact of the tumor microenvironment, specifically matrix stiffness, on treatment response in patient-derived PDAC organoids.
- To elucidate mechanisms of drug resistance and identify strategies for overcoming therapeutic resistance in PDAC.
Main Methods:
- Patient-derived PDAC cells (G43, G46) were cultured in a 3D organoid system with tunable stiffness.
- Organoids were treated with gemcitabine, Gemcitabine-8C, AZD 1775, or their combination.
- Efficacy, extracellular matrix influence, morphology, gene expression, and resistance mechanisms were assessed.
Main Results:
- The combination of AZD 1775 and Gemcitabine-8C significantly improved treatment efficacy compared to monotherapies.
- Tumor matrix stiffness correlated positively with drug resistance; G43 cells were more sensitive than G46 cells.
- Resistant cells showed increased oxidative stress, while sensitive cells displayed F-actin alterations.
Conclusions:
- AZD 1775 potentiates Gemcitabine-8C efficacy at non-toxic doses, suggesting a strategy to overcome PDAC treatment resistance.
- Cell origin and tumor microenvironment significantly modulate drug response, emphasizing the need for personalized and microenvironment-targeted strategies.
- This combination therapy holds potential for improving outcomes in pancreatic cancer patients.
