Molecular Pathology Group, Vall d'Hebron Research Institute, Universidad Autonoma of Barcelona, Barcelona, Spain.
PLoS One. 2013;8(1):e53645. doi: 10.1371/journal.pone.0053645. Epub 2013 Jan 8.
Elisidepsin (elisidepsin trifluoroacetate, Irvalec®, PM02734) is a new synthetic depsipeptide, a result of the PharmaMar Development Program that seeks synthetic products of marine origin-derived compounds. Elisidepsin is a drug with antiproliferative activity in a wide range of tumors. In the present work we studied and characterized the mechanisms associated with sensitivity and resistance to elisidepsin treatment in a broad panel of tumor cell lines from breast and pancreas carcinomas, focusing on different factors involved in epithelial-mesenchymal transition (EMT) and the use of HER family receptors in predicting the in vitro drug response. Interestingly, we observed that the basal protein expression levels of EMT markers show a significant correlation with cell viability in response to elisidepsin treatment in a panel of 12 different breast and pancreatic cancer cell lines. In addition, we generated three elisidepsin treatment-resistant cell lines (MCF-7, HPAC and AsPC-1) and analyzed the pattern of expression of different EMT markers in these cells, confirming that acquired resistance to elisidepsin is associated with a switch to the EMT state. Furthermore, a direct correlation between basal HER3 expression and sensitivity to elisidepsin was observed; moreover, modulation of HER3 expression levels in different cancer cell lines alter their sensitivities to the drug, making them more resistant when HER3 expression is downregulated by a HER3-specific short hairpin RNA and more sensitive when the receptor is overexpressed. These results show that HER3 expression is an important marker of sensitivity to elisidepsin treatment.
依沙匹隆（依沙匹隆三氟乙酸盐，Irvalec®，PM02734）是一种新型合成的脂肽，是 PharmaMar 开发计划的产物，该计划旨在寻找源自海洋的合成产物。依沙匹隆是一种具有广泛抗肿瘤活性的药物。在本工作中，我们研究并阐明了与广泛的乳腺癌和胰腺癌肿瘤细胞系对依沙匹隆治疗的敏感性和耐药性相关的机制，重点关注上皮-间质转化（EMT）相关的不同因素和 HER 家族受体在预测体外药物反应中的作用。有趣的是，我们观察到，在一组 12 种不同的乳腺癌和胰腺癌细胞系中，EMT 标志物的基础蛋白表达水平与细胞对依沙匹隆治疗的存活率呈显著相关性。此外，我们还生成了三种依沙匹隆耐药细胞系（MCF-7、HPAC 和 AsPC-1），并分析了这些细胞中不同 EMT 标志物的表达模式，证实获得性耐药与 EMT 状态的转变有关。此外，我们观察到基础 HER3 表达与对依沙匹隆的敏感性之间存在直接相关性；此外，在不同的癌细胞系中调节 HER3 表达水平会改变它们对药物的敏感性，当 HER3 表达被 HER3 特异性短发夹 RNA 下调时，细胞会变得更耐药，而当受体过表达时，细胞会变得更敏感。这些结果表明，HER3 表达是对依沙匹隆治疗敏感性的一个重要标志物。
