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A Novel Gemcitabine-Resistant Gallbladder Cancer Model Provides Insights into Molecular Changes Occurring during
Luis Vergara-Gómez1, Carolina Bizama2,3, Jun Zhong4
1Biomedicine and Translational Research Laboratory, Centre of Excellence in Translational Medicine and Scientific and Technological Bioresource Nucleus (CEMT-BIOREN), Universidad de La Frontera, Temuco 4810296, Chile.
Abstract:
Treatment options for advanced gallbladder cancer (GBC) are scarce and usually rely on cytotoxic chemotherapy, but the effectiveness of any regimen is limited and recurrence rates are high. Here, we investigated the molecular mechanisms of acquired resistance in GBC through the development and characterization of two gemcitabine-resistant GBC cell sublines (NOZ GemR and TGBC1 GemR). Morphological changes, cross-resistance, and migratory/invasive capabilities were evaluated. Then, microarray-based transcriptome profiling and quantitative SILAC-based phosphotyrosine proteomic analyses were performed to identify biological processes and signaling pathways dysregulated in gemcitabine-resistant GBC cells. The transcriptome profiling of parental and gemcitabine-resistant cells revealed the dysregulation of protein-coding genes that promote the enrichment of biological processes such as epithelial-to-mesenchymal transition and drug metabolism. On the other hand, the phosphoproteomics analysis of NOZ GemR identified aberrantly dysregulated signaling pathways in resistant cells as well as active kinases, such as ABL1, PDGFRA, and LYN, which could be novel therapeutic targets in GBC. Accordingly, NOZ GemR showed increased sensitivity toward the multikinase inhibitor dasatinib compared to parental cells. Our study describes transcriptome changes and altered signaling pathways occurring in gemcitabine-resistant GBC cells, which greatly expands our understanding of the underlying mechanisms of acquired drug resistance in GBC.
Insights
Researchers explored how gallbladder cancer (GBC) cells become resistant to gemcitabine chemotherapy. They identified key molecular changes and potential new drug targets, like specific kinases, offering hope for improved GBC treatment.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Advanced gallbladder cancer (GBC) has limited treatment options and high recurrence rates.
- Cytotoxic chemotherapy, like gemcitabine, shows limited effectiveness against GBC.
- Understanding acquired drug resistance mechanisms is crucial for developing better therapies.
Purpose of the Study:
- To investigate the molecular mechanisms underlying acquired gemcitabine resistance in GBC.
- To identify novel therapeutic targets in gemcitabine-resistant GBC cells.
- To characterize transcriptome and phosphoproteome alterations in resistant GBC models.
Main Methods:
- Development and characterization of gemcitabine-resistant GBC cell sublines (NOZ GemR, TGBC1 GemR).
- Microarray-based transcriptome profiling to analyze gene expression changes.
- Quantitative SILAC-based phosphotyrosine proteomic analysis to identify signaling pathway dysregulation.
Main Results:
- Gemcitabine-resistant GBC cells exhibited altered morphology, cross-resistance, and increased migratory/invasive capabilities.
- Transcriptome analysis revealed dysregulation of genes involved in epithelial-to-mesenchymal transition and drug metabolism.
- Phosphoproteomics identified active kinases (ABL1, PDGFRA, LYN) in resistant cells, with increased sensitivity to dasatinib.
Conclusions:
- Acquired gemcitabine resistance in GBC involves significant transcriptome and signaling pathway alterations.
- Specific kinases like ABL1, PDGFRA, and LYN represent potential therapeutic targets for overcoming resistance.
- Targeting these pathways may offer new strategies for treating advanced GBC.
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