Font Albert, Ruiz de Porras Vicenç, Valderrama Begoña P, Ramirez Jose Luis, Nonell Lara, Virizuela José Antonio, Anido Urbano, González-Del-Alba Aránzazu, Lainez Nuria, Llorente Maria Del Mar, Jiménez Natalia, Mellado Begoña, García-Donas Jesus, Bellmunt Joaquim
Department of Medical Oncology, Catalan Institute of Oncology, University Hospital Germans Trias i Pujol, Ctra. Can Ruti-Camí de les Escoles s/n, 08916 Badalona, Spain.
Catalan Institute of Oncology, Badalona Applied Research Group in Oncology (B·ARGO), Ctra. Can Ruti-Camí de les Escoles s/n, 08916 Badalona, Spain.
Cancers (Basel). 2021 Dec 12;13(24):6235. doi: 10.3390/cancers13246235.
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.
在II期MAJA试验中，对于一线铂类化疗后未进展的晚期尿路上皮癌（aUCC）患者，与最佳支持治疗相比，长春氟宁维持治疗可带来更长的无进展生存期。然而，尽管在一些患者中观察到了初始获益，但明确的耐药性仍然出现，其潜在机制目前尚不清楚。我们进行了基因表达和功能富集分析，以阐明这些潜在耐药机制的发现。分析了MAJA试验中8例对长春氟宁预后不良和9例预后良好患者的差异基因表达谱。从肿瘤组织中分离RNA，并通过微阵列评估基因表达。用微阵列数据的线性模型确定差异表达。基因集富集分析（GSEA）用于基因的功能分类。使用尿路上皮癌细胞系进行体外功能研究。层次聚类显示长春氟宁治疗预后良好和不良患者之间存在差异基因表达模式。GSEA确定上皮-间质转化（EMT）是预后良好患者中最显著负富集的特征。体外分析表明，多酚姜黄素下调EMT标志物并使尿路上皮癌细胞对长春氟宁敏感。我们得出结论，EMT介导对长春氟宁的耐药性，并表明逆转这一过程可增强长春氟宁在aUCC患者中的疗效。
