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Article

Molecular and Functional Analysis of Sunitinib-Resistance Induction in Human Renal Cell Carcinoma Cells

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, 1205 Geneva, Switzerland
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iGE3 Genomics Platform, University of Geneva, 1206 Geneva, Switzerland
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Department of Genetics and Evolution, University of Geneva, 1205 Geneva, Switzerland
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Department of Visceral Surgery, Lausanne University Hospital and University of Lausanne, 1015 Lausanne, Switzerland
*
Author to whom correspondence should be addressed.
Academic Editor: Ahmad R. Safa
Int. J. Mol. Sci. 2021, 22(12), 6467; https://doi.org/10.3390/ijms22126467
Received: 2 May 2021 / Revised: 24 May 2021 / Accepted: 11 June 2021 / Published: 16 June 2021
(This article belongs to the Section Biochemistry)
Resistance in clear cell renal cell carcinoma (ccRCC) against sunitinib is a multifaceted process encompassing numerous molecular aberrations. This induces clinical complications, reducing the treatment success. Understanding these aberrations helps us to select an adapted treatment strategy that surpasses resistance mechanisms, reverting the treatment insensitivity. In this regard, we investigated the dominant mechanisms of resistance to sunitinib and validated an optimized multidrug combination to overcome this resistance. Human ccRCC cells were exposed to single or chronic treatment with sunitinib to obtain three resistant clones. Upon manifestation of sunitinib resistance, morphometric changes in the cells were observed. At the molecular level, the production of cell membrane and extracellular matrix components, chemotaxis, and cell cycle progression were dysregulated. Molecules enforcing the cell cycle progression, i.e., cyclin A, B1, and E, were upregulated. Mass spectrometry analysis revealed the intra- and extracellular presence of N-desethyl sunitinib, the active metabolite. Lysosomal sequestration of sunitinib was confirmed. After treatment with a synergistic optimized drug combination, the cell metabolic activity in Caki-1-sunitinib-resistant cells and 3D heterotypic co-cultures was reduced by >80%, remaining inactive in non-cancerous cells. These results demonstrate geno- and phenotypic changes in response to sunitinib treatment upon resistance induction. Mimicking resistance in the laboratory served as a platform to study drug responses. View Full-Text
Keywords: acquired drug resistance; (clear cell) renal cell carcinoma; drug combination; isomerization; metabolites; sunitinib acquired drug resistance; (clear cell) renal cell carcinoma; drug combination; isomerization; metabolites; sunitinib
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MDPI and ACS Style

Rausch, M.; Rutz, A.; Allard, P.-M.; Delucinge-Vivier, C.; Docquier, M.; Dormond, O.; Wolfender, J.-L.; Nowak-Sliwinska, P. Molecular and Functional Analysis of Sunitinib-Resistance Induction in Human Renal Cell Carcinoma Cells. Int. J. Mol. Sci. 2021, 22, 6467. https://doi.org/10.3390/ijms22126467

AMA Style

Rausch M, Rutz A, Allard P-M, Delucinge-Vivier C, Docquier M, Dormond O, Wolfender J-L, Nowak-Sliwinska P. Molecular and Functional Analysis of Sunitinib-Resistance Induction in Human Renal Cell Carcinoma Cells. International Journal of Molecular Sciences. 2021; 22(12):6467. https://doi.org/10.3390/ijms22126467

Chicago/Turabian Style

Rausch, Magdalena, Adriano Rutz, Pierre-Marie Allard, Céline Delucinge-Vivier, Mylène Docquier, Olivier Dormond, Jean-Luc Wolfender, and Patrycja Nowak-Sliwinska. 2021. "Molecular and Functional Analysis of Sunitinib-Resistance Induction in Human Renal Cell Carcinoma Cells" International Journal of Molecular Sciences 22, no. 12: 6467. https://doi.org/10.3390/ijms22126467

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