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A Data Integration Workflow to Identify Drug Combinations Targeting Synthetic Lethal Interactions
Published on: May 27, 2021
Synthetic lethal hubs associated with vincristine resistant neuroblastoma
Raul Fechete1, Susanne Barth, Tsviya Olender
1Emergentec Biodevelopment GmbH, Gersthofer Strasse 29-31, 1180 Vienna, Austria.
Abstract:
Chemotherapy of cancer experiences a number of shortcomings including development of drug resistance. This fact also holds true for neuroblastoma utilizing chemotherapeutics as vincristine. We performed a comparative analysis of molecular and cellular mechanisms associated with vincristine resistance utilizing cell line as well as human tissue data. Differential gene expression analysis revealed molecular features, processes and pathways afflicted with drug resistance mechanisms in general, and specifically with vincristine significantly involving actin associated features. However, specific mode of resistance as well as underlying genotype of parental, vincristine sensitive cells apparently exhibited significant heterogeneity. No consensus profile for vincristine resistance could be derived, but resistance-associated changes on the level of individual neuroblastoma cell lines as well as individual patient profiles became clearly evident. Based on these prerequisites we utilized the concept of synthetic lethality aimed at identifying hub proteins which when inhibited promise to induce cell death due to a synthetic lethal interaction with down-regulated, chemoresistance associated features. Our screening procedure identified synthetic lethal hub proteins afflicted with actin associated processes holding synthetic lethal interactions to down-regulated features individually found in all chemoresistant cell lines tested, therefore promising an improved therapeutic window. Verification of such synthetic lethal hub candidates in human neuroblastoma tissue expression profiles indicated the feasibility of this screening approach for addressing vincristine resistance in neuroblastoma.
Insights
Vincristine resistance in neuroblastoma is complex and heterogeneous. Targeting synthetic lethal hub proteins, particularly those linked to actin processes, offers a promising strategy to overcome chemoresistance.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Chemotherapy, including vincristine for neuroblastoma, faces challenges due to drug resistance.
- Understanding the molecular and cellular mechanisms of vincristine resistance is crucial for improving treatment outcomes.
Purpose of the Study:
- To comparatively analyze mechanisms of vincristine resistance in neuroblastoma using cell line and human tissue data.
- To identify novel therapeutic targets through synthetic lethality to overcome vincristine resistance.
Main Methods:
- Differential gene expression analysis to identify resistance-associated molecular features.
- Application of synthetic lethality principles to screen for targetable hub proteins.
- Validation of identified targets in human neuroblastoma tissue expression profiles.
Main Results:
- Vincristine resistance mechanisms involve actin-associated features and exhibit significant heterogeneity.
- No single consensus profile for vincristine resistance was identified.
- Synthetic lethal hub proteins interacting with chemoresistance-associated features were identified, particularly those involving actin processes.
Conclusions:
- Vincristine resistance in neuroblastoma is characterized by individual cell line and patient-specific profiles.
- Targeting identified synthetic lethal hub proteins shows potential for a more effective therapeutic window in neuroblastoma.
- The synthetic lethality screening approach is feasible for addressing vincristine resistance in neuroblastoma.
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