Chromosome 20q amplification regulates in vitro response to Kinesin-5 inhibitor. Homo sapiens

We identified gene expression signatures predicting responsiveness to a Kinesin-5 (kinesin spindle protein, KIF11) inhibitor (Kinesin-5i) in cultured colon tumor cell lines. Genes predicting resistance to Kinesin-5i were enriched for those from chromosome 20q, a region of frequent amplification in a number of tumor types. siRNAs targeting genes in this chromosomal region identified AURKA, TPX2 and MYBL2 as genes whose disruption enhances response to Kinesin-5i. Taken together, our results show functional interaction between these genes, and suggest that overexpression of AURKA, TPX2 and MYBL2 is functionally involved in resistance to Kinesin-5i. Furthermore, our results suggest that patients whose tumors overexpress AURKA due to amplifications of 20q will be more likely to resist treatment with Kinesin-5 inhibitor, and that inactivation of AURKA may sensitize these patients to treatment. Keywords: Cell line comparison Overall design: A series of colon cancer cell lines was analyzed for gene expression signatures. These gene expression signatures were then correlated with in vitro responsiveness of each cell line to a KSP inhibitor (Kinesin-5i). Transcripts whose expression was correlated with response (>0.5 or <-0.5) were identified as reporters of cellular response to this inhibitor. Reporters were further tested by RNAi for functional role in response to this inhibitor.

我们在体外培养的结肠肿瘤细胞系中，鉴定出可预测对驱动蛋白-5（Kinesin-5，亦称驱动蛋白纺锤体蛋白KIF11）抑制剂（Kinesin-5i）响应的基因表达特征。可预测对Kinesin-5i产生耐药性的基因，在20号染色体长臂（20q）区域的基因中显著富集；该区域在多种肿瘤类型中常发生扩增。靶向该染色体区域基因的小干扰RNA（siRNA）实验证实，AURKA、TPX2及MYBL2这三个基因的敲低可增强细胞对Kinesin-5i的响应。综上，本研究结果证实了上述基因间存在功能互作，并表明AURKA、TPX2及MYBL2的过表达在功能上参与了对Kinesin-5i的耐药过程。此外，本研究结果提示，因20q区域扩增而导致AURKA过表达的肿瘤患者，更有可能对Kinesin-5抑制剂治疗产生耐药；而AURKA的失活可使此类患者对治疗产生敏感性。
关键词：细胞系比较
整体实验设计：本研究对一系列结肠癌细胞系的基因表达特征进行了分析，并将这些基因表达特征与各细胞系体外对KSP抑制剂（即Kinesin-5i）的响应能力进行关联分析。将表达水平与响应程度相关系数绝对值大于0.5的转录本鉴定为该抑制剂细胞响应的标志物。随后通过RNA干扰（RNAi）实验进一步验证这些标志物在该抑制剂响应过程中的功能作用。