Drug Repurposing to Identify a Synergistic High-Order Drug Combination to Treat Sunitinib-Resistant Renal Cell Carcinoma.
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6 août 2021
- doi: 10.3390/cancers13163978
- issn: 2072-6694
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info:eu-repo/semantics/altIdentifier/doi/10.3390/cancers13163978
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info:eu-repo/semantics/altIdentifier/pmid/34439134
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info:eu-repo/semantics/altIdentifier/pissn/2072-6694
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info:eu-repo/semantics/altIdentifier/urn/urn:nbn:ch:serval-BIB_3704D6CA4FBB0
info:eu-repo/semantics/openAccess , CC BY 4.0 , https://creativecommons.org/licenses/by/4.0/
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Primary metabolism Anabolism Metabolism, Primary Catabolism Medications Medicaments Prescription drugs Medicines (Drugs) Pharmaceuticals Medicine (Drugs)Citer ce document
M. Rausch et al., « Drug Repurposing to Identify a Synergistic High-Order Drug Combination to Treat Sunitinib-Resistant Renal Cell Carcinoma. », Serveur académique Lausannois, ID : 10.3390/cancers13163978
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Résumé
Repurposed drugs have been evaluated for the management of clear cell renal cell carcinoma (ccRCC), but only a few have influenced the overall survival of patients with advanced disease. To combine repurposed non-oncology with oncological drugs, we applied our validated phenotypic method, which consisted of a reduced experimental part and data modeling. A synergistic optimized multidrug combination (ODC) was identified to significantly reduce the energy levels in cancer remaining inactive in non-cancerous cells. The ODC consisted of Rapta-C, erlotinib, metformin and parthenolide and low doses. Molecular and functional analysis of ODC revealed a loss of adhesiveness and induction of apoptosis. Gene-expression network analysis displayed significant alterations in the cellular metabolism, confirmed by LC-MS based metabolomic analysis, highlighting significant changes in the lipid classes. We used heterotypic in vitro 3D co-cultures and ex vivo organoids to validate the activity of the ODC, maintaining an efficacy of over 70%. Our results show that repurposed drugs can be combined to target cancer cells selectively with prominent activity. The strong impact on cell adherence and metabolism indicates a favorable mechanism of action of the ODC to treat ccRCC.