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

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License: CC BY 4.0
Serval ID
serval:BIB_A38F3BC4CD1B
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Molecular and Functional Analysis of Sunitinib-Resistance Induction in Human Renal Cell Carcinoma Cells.
Journal
International journal of molecular sciences
Author(s)
Rausch M., Rutz A., Allard P.M., Delucinge-Vivier C., Docquier M., Dormond O., Wolfender J.L., Nowak-Sliwinska P.
ISSN
1422-0067 (Electronic)
ISSN-L
1422-0067
Publication state
Published
Issued date
16/06/2021
Peer-reviewed
Oui
Volume
22
Number
12
Pages
6467
Language
english
Notes
Publication types: Journal Article
Publication Status: epublish
Abstract
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.
Keywords
(clear cell) renal cell carcinoma, acquired drug resistance, drug combination, isomerization, metabolites, sunitinib
Pubmed
Web of science
Open Access
Yes
Create date
09/07/2021 9:26
Last modification date
23/11/2022 6:50
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