文章：

基因表达特征与两种酪氨酸激酶抑制剂尼罗替尼和伊马替尼的体外抗性相关

Gene expression signatures associated with the in vitro resistance to two tyrosine kinase inhibitors, nilotinib and imatinib

原文发布日期：2011-08-26

DOI: 10.1038/bcj.2011.32

类型: Original Article

开放获取: 是

英文摘要：

The use of selective inhibitors targeting Bcr-Abl kinase is now established as a standard protocol in the treatment of chronic myelogenous leukemia; however, the acquisition of drug resistance is a major obstacle limiting the treatment efficacy. To elucidate the molecular mechanism of drug resistance, we established K562 cell line models resistant to nilotinib and imatinib. Microarray-based transcriptome profiling of resistant cells revealed that nilotinib- and imatinib-resistant cells showed the upregulation of kinase-encoding genes (AURKC, FYN, SYK, BTK and YES1). Among them, the upregulation of AURKC and FYN was observed both in nilotinib- and imatinib-resistant cells irrespective of exposure doses, while SYK, BTK and YES1 showed dose-dependent upregulation of expression. Upregulation of EGF and JAG1 oncogenes as well as genes encoding ATP-dependent drug efflux pump proteins such as ABCB1 was also observed in the resistant cells, which may confer alternative survival benefits. Functional gene set analysis revealed that molecular categories of ‘ATPase activity’, ‘cell adhesion’ or ‘tyrosine kinase activity’ were commonly activated in the resistant clones. Taken together, the transcriptome analysis of tyrosine kinase inhibitors (TKI)-resistant clones provides the insights into the mechanism of drug resistance, which can facilitate the development of an effective screening method as well as therapeutic intervention to deal with TKI resistance.

摘要翻译： 

靶向Bcr-Abl激酶的选择性抑制剂的应用已成为慢性髓系白血病治疗的标准方案，然而耐药性的产生是限制治疗效果的主要障碍。为阐明耐药分子机制，我们建立了尼洛替尼和伊马替尼耐药的K562细胞系模型。基于微阵列的耐药细胞转录组分析显示，尼洛替尼和伊马替尼耐药细胞中激酶编码基因（AURKC、FYN、SYK、BTK和YES1）表达上调。其中，AURKC和FYN的上调在尼洛替尼和伊马替尼耐药细胞中均出现且与暴露剂量无关，而SYK、BTK和YES1则呈现剂量依赖性表达上调。耐药细胞中还观察到EGF和JAG1癌基因以及ABCB1等ATP依赖性药物外排泵蛋白编码基因的上调，这可能赋予细胞替代性生存优势。功能基因集分析显示“ATP酶活性”“细胞黏附”或“酪氨酸激酶活性”等分子类别在耐药克隆中被共同激活。综合而言，对酪氨酸激酶抑制剂（TKI）耐药克隆的转录组分析为耐药机制提供了新见解，有助于开发有效的筛查方法及治疗干预策略以应对TKI耐药。

原文链接：

Gene expression signatures associated with the in vitro resistance to two tyrosine kinase inhibitors, nilotinib and imatinib