2. Academic Validation
  3. Drug Repurposing to Identify a Synergistic High-Order Drug Combination to Treat Sunitinib-Resistant Renal Cell Carcinoma

Drug Repurposing to Identify a Synergistic High-Order Drug Combination to Treat Sunitinib-Resistant Renal Cell Carcinoma

  • Cancers (Basel). 2021 Aug 6;13(16):3978. doi: 10.3390/cancers13163978.
Magdalena Rausch 1 2 3,  Adriano Rutz 1 2,  Pierre-Marie Allard 1 2,  Céline Delucinge-Vivier 4,  Mylène Docquier 4 5,  Olivier Dormond 6,  Paul J Dyson 7,  Jean-Luc Wolfender 1 2,  Patrycja Nowak-Sliwinska 1 2 3
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, University of Geneva, CMU-Rue Michel-Servet 1, CH-1211 Geneva, Switzerland.
  • 2 Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, CMU-Rue Michel-Servet 1, CH-1211 Geneva, Switzerland.
  • 3 Translational Research Center in Oncohaematology, CH-1211 Geneva, Switzerland.
  • 4 GE3 Genomics Platform, University of Geneva, CH-1211 Geneva, Switzerland.
  • 5 Department of Genetics and Evolution, University of Geneva, CH-1211 Geneva, Switzerland.
  • 6 Department of Visceral Surgery, Lausanne University Hospital and University of Lausanne, 1015 Lausanne, Switzerland.
  • 7 Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
PMID: 34439134 DOI: 10.3390/cancers13163978
Abstract

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.

Keywords

Rapta-C; drug combination; drug repurposing; drug-drug interaction; metabolism; metformin; synergistic.

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