Epithelial-to-mesenchymal transition mediates resistance to maintenance therapy with vinflunine in advanced urothelial cell carcinoma
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- dc.contributor.author Font, Albert
- dc.contributor.author Ruiz de Porras, Vicenç
- dc.contributor.author Valderrama, Begoña P.
- dc.contributor.author Ramirez, Jose Luis
- dc.contributor.author Nonell Mazelon, Lara, 1972-
- dc.contributor.author Virizuela, José Antonio
- dc.contributor.author Anido, Urbano
- dc.contributor.author González-Del-Alba, Aránzazu
- dc.contributor.author Lainez, Nuria
- dc.contributor.author Llorente, Maria Del Mar
- dc.contributor.author Jiménez, Natalia
- dc.contributor.author Mellado, Begoña
- dc.contributor.author García-Donas, Jesús
- dc.contributor.author Bellmunt Molins, Joaquim, 1959-
- dc.date.accessioned 2022-08-03T15:23:21Z
- dc.date.available 2022-08-03T15:23:21Z
- dc.date.issued 2021
- dc.description.abstract In the phase II MAJA trial, maintenance therapy with vinflunine resulted in longer progression-free survival compared to best supportive care in advanced urothelial cell carcinoma (aUCC) patients who did not progress after first-line platinum-based chemotherapy. However, despite an initial benefit observed in some patients, unequivocal resistance appears which underlying mechanisms are presently unknown. We have performed gene expression and functional enrichment analyses to shed light on the discovery of these underlying resistance mechanisms. Differential gene expression profile of eight patients with poor outcome and nine with good outcome to vinflunine administered in the MAJA trial were analyzed. RNA was isolated from tumor tissue and gene expression was assessed by microarray. Differential expression was determined with linear models for microarray data. Gene Set Enrichment Analysis (GSEA) was used for the functional classification of the genes. In vitro functional studies were performed using UCC cell lines. Hierarchical clustering showed a differential gene expression pattern between patients with good and poor outcome to vinflunine treatment. GSEA identified epithelial-to-mesenchymal transition (EMT) as the top negatively enriched hallmark in patients with good outcome. In vitro analyses showed that the polyphenol curcumin downregulated EMT markers and sensitized UCC cells to vinflunine. We conclude that EMT mediates resistance to vinflunine and suggest that the reversion of this process could enhance the effect of vinflunine in aUCC patients.
- dc.format.mimetype application/pdf
- dc.identifier.citation Font A, Ruiz de Porras V, Valderrama BP, Ramirez JL, Nonell L, Virizuela JA, Anido U, González-Del-Alba A, Lainez N, Llorente MDM, Jiménez N, Mellado B, García-Donas J, Bellmunt J. Epithelial-to-mesenchymal transition mediates resistance to maintenance therapy with vinflunine in advanced urothelial cell carcinoma. Cancers (Basel). 2021 Dec 12;13(24):6235. DOI: 10.3390/cancers13246235
- dc.identifier.doi http://dx.doi.org/10.3390/cancers13246235
- dc.identifier.issn 2072-6694
- dc.identifier.uri http://hdl.handle.net/10230/53914
- dc.language.iso eng
- dc.publisher MDPI
- dc.relation.ispartof Cancers (Basel). 2021 Dec 12;13(24):6235
- dc.rights © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
- dc.rights.accessRights info:eu-repo/semantics/openAccess
- dc.rights.uri https://creativecommons.org/licenses/by/4.0/
- dc.subject.keyword Advanced urothelial cell carcinoma
- dc.subject.keyword Chemotherapy resistance
- dc.subject.keyword Epithelial-to-mesenchymal transition
- dc.subject.keyword Maintenance therapy
- dc.subject.keyword Vinflunine
- dc.title Epithelial-to-mesenchymal transition mediates resistance to maintenance therapy with vinflunine in advanced urothelial cell carcinoma
- dc.type info:eu-repo/semantics/article
- dc.type.version info:eu-repo/semantics/publishedVersion