Blood Cancer J. 2011 Aug;1(8):e32. doi: 10.1038/bcj.2011.32. Epub 2011 Aug 26.
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.
针对 Bcr-Abl 激酶的选择性抑制剂的使用现已成为治疗慢性髓性白血病的标准方案；然而，获得耐药性是限制治疗效果的主要障碍。为了阐明耐药性的分子机制，我们建立了对尼罗替尼和伊马替尼耐药的 K562 细胞系模型。耐药细胞的基于微阵列的转录组谱分析显示，尼罗替尼和伊马替尼耐药细胞上调了编码激酶的基因（AURKC、FYN、SYK、BTK 和 YES1）。其中，AURKC 和 FYN 的上调在无论暴露剂量如何，在尼罗替尼和伊马替尼耐药细胞中均观察到，而 SYK、BTK 和 YES1 的表达则呈剂量依赖性上调。耐药细胞中还观察到 EGF 和 JAG1 癌基因以及编码 ATP 依赖性药物外排泵蛋白的基因（如 ABCB1）的上调，这可能赋予了替代的生存优势。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普遍被激活。总之，对酪氨酸激酶抑制剂（TKI）耐药克隆的转录组分析提供了对耐药机制的深入了解，这有助于开发有效的筛选方法以及治疗干预措施来应对 TKI 耐药性。
