en
Scientific article
Open access
English

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

Published inInternational journal of molecular sciences, vol. 22, no. 12, 6467
Publication date2021-06-16
First online date2021-06-16
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
  • Acquired drug resistance
  • Drug combination
  • Isomerization
  • Metabolites
  • Sunitinib
  • Renal cell carcinoma
Citation (ISO format)
RAUSCH, Magdalena et al. Molecular and Functional Analysis of Sunitinib-Resistance Induction in Human Renal Cell Carcinoma Cells. In: International journal of molecular sciences, 2021, vol. 22, n° 12, p. 6467. doi: 10.3390/ijms22126467
Main files (1)
Article (Published version)
Identifiers
ISSN of the journal1422-0067
136views
79downloads

Technical informations

Creation01/20/2022 8:40:00 AM
First validation01/20/2022 8:40:00 AM
Update time03/16/2023 2:43:17 AM
Status update03/16/2023 2:43:16 AM
Last indexation05/06/2024 10:00:46 AM
All rights reserved by Archive ouverte UNIGE and the University of GenevaunigeBlack