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Epithelial-to-mesenchymal transition mediates resistance to maintenance therapy with vinflunine in advanced urothelial cell carcinoma patients

ABSTRACT: Epithelial-to-mesenchymal transition mediates resistance to maintenance therapy with vinflunine in advanced urothelial cell carcinoma patients

PROVIDER: PRJNA752283 | ENA |

REPOSITORIES: ENA

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Project description:Urothelial cell carcinoma (UCC) is the fifth most common type of cancer in developed countries. Vinflunine, a third-generation semi-synthetic anti-microtubule agent, was approved in 2009 by the EMA for the treatment of patients with advanced UCC (aUCC) who have progressed after initial treatment with a platinum-based chemotherapy regimen. However, nowadays with the incorporation of immune-checkpoint blockade in the management of aUCC, vinflunine is considered as a third line treatment after immunotherapy failure. In the randomized phase II MAJA trial we demonstrated that maintenance therapy with vinflunine in patients with controlled disease after first-line platinum-based chemotherapy resulted in significantly longer progression-free survival as compared to best supportive care. However, at present, the mechanisms that underlying vinflunine resistance in UCC remain unclear. Thus, the objective of this study is to perform a pre-planned gene expression analyses aimed to identify new resistance mechanisms as well as biomarkers to predict response to maintenance vinflunine. We have compared the gene expression profiles of eight bad responders to vinflunine (<4 cycles) and nine good responders (>12 cycles). RNA was isolated from FFPE tumor tissue collected using the Covaris kit and gene expression levels were analyzed with Clariom S (Affymetrix). Differential expression, defined as p<0.05 and |FC|>1.5, was determined with linear models for microarray data included in the limma and sva packages. Pre-ranked Gene Set Enrichment Analysis (GSEA) was used for the functional classification of the differential expression genes. In vitro validation was performed using bladder cancer cell lines. Hierarchical clustering of genes showed a differential expression pattern between good and bad responders. In good responders, GSEA revealed that “Epithelial-to-mesenchymal transition” (EMT) and “IL-6 – JAK – STAT3” pathways were the top enriched negatively hallmarks. Mechanistically, we showed that the downregulation of mesenchymal markers using the polyphenol curcumin, a well-known EMT inhibitor, significantly sensitized mesenchymal-like bladder cancer cells to vinflunine treatment. In conclusion, our results demonstrated that EMT process mediates resistance to vinflunine and suggested that the combination of this anti-microtubule agent with an EMT inhibitor could be a good strategy of maintenance therapy in aUCC patients.

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Epithelial-to-mesenchymal transition mediates resistance to maintenance therapy with vinflunine in advanced urothelial cell carcinoma patients

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