RT Journal Article
T1 Epithelial-to-Mesenchymal Transition Mediates Resistance to Maintenance Therapy with Vinflunine in Advanced Urothelial Cell Carcinoma.
A1 Font, Albert
A1 Ruiz de Porras, Vicenç
A1 Valderrama, Begoña P
A1 Ramirez, Jose Luis
A1 Nonell, Lara
A1 Virizuela, José Antonio
A1 Anido, Urbano
A1 González-Del-Alba, Aránzazu
A1 Lainez, Nuria
A1 Llorente, Maria Del Mar
A1 Jiménez, Natalia
A1 Mellado, Begoña
A1 García-Donas, Jesus
A1 Bellmunt, Joaquim
K1 advanced urothelial cell carcinoma
K1 chemotherapy resistance
K1 epithelial-to-mesenchymal transition
K1 maintenance therapy
K1 vinflunine
AB 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.
SN 2072-6694
YR 2021
FD 2021-12-12
LK https://hdl.handle.net/10668/26370
UL https://hdl.handle.net/10668/26370
LA en
DS RISalud
RD Apr 5, 2025