Epithelial-to-Mesenchymal Transition Mediates Resistance to Maintenance Therapy with Vinflunine in Advanced Urothelial Cell Carcinoma

SIMPLE SUMMARY: Platinum-based chemotherapy is the first-line treatment for advanced urothelial cell carcinoma (aUCC). After first-line treatment, we previously showed that maintenance therapy with vinflunine improves progression-free survival. However, some patients are resistant to vinflunine and the specific mechanisms of resistance in aUCC are unclear. We analyzed the genomic landscape and the biological processes potentially related to vinflunine activity and found that epithelial-to-mesenchymal transition (EMT) plays a pivotal role as a resistance mechanism. In experiments with cell lines, curcumin reversed EMT and sensitized cells to vinflunine. We suggest that EMT mediates resistance to vinflunine and that the reversion of this process could enhance the effect of vinflunine in aUCC patients. 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.