Identification of genes that confer tumor cell resistance to the Aurora B kinase inhibitor, AZD1152
Identification of genes that confer tumor cell resistance to the Aurora B kinase inhibitor, AZD1152
复制标题
DOI：
10.1038/tpj.2008.20
复制
发表时间：
2009-04-01
影响因子：
2.8
通讯作者：
Shah, O. J.
中科院分区：
文献类型：
--
作者：
Guo, J.;Anderson, M. G.;Shah, O. J.
AZD 1152是一种高选择性极光B激酶抑制剂，目前正在急性髓性白血病和晚期实体恶性肿瘤患者中进行I期和II期临床评价。我们已经从SW 620结肠癌和MiaPaCa胰腺癌细胞系中建立了两种AZD 1152耐药细胞系，它们对AZD 1152的活性代谢产物AZD 1152 HQPA耐药> 100倍，有趣的是，对泛极光激酶抑制剂VX-680/MK 0457交叉耐药。使用全基因组微阵列分析和比较基因组杂交，我们能够确定MDR 1和BCRP作为这些模型中AZD 1152 HQPA耐药的致病基因。此外，这些基因中任一个的上调足以使体内肿瘤生长对AZD 1152不敏感。最后，MDR 1或BCRP的上调可预测肿瘤细胞对该药物的体外和体内敏感性。这些数据为Aurora激酶抑制剂的耐药性提供了遗传基础，可用于预测对治疗的临床反应。
AZD1152 is a highly selective Aurora B kinase inhibitor currently undergoing Phase I and II clinical evaluation in patients with acute myelogenous leukemia and advanced solid malignancies. We have established two AZD1152-resistant cell lines from SW620 colon and MiaPaCa pancreatic carcinoma lines, which are > 100-fold resistant to the active metabolite of AZD1152, AZD1152 HQPA and interestingly, cross-resistant to the pan-Aurora kinase inhibitor, VX-680/MK0457. Using whole-genome microarray analysis and comparative genomic hybridization, we were able to identify MDR1 and BCRP as the causative genes that underlie AZD1152 HQPA-resistance in these models. Furthermore, the upregulation of either of these genes is sufficient to render in vivo tumor growth insensitive to AZD1152. Finally, the upregulation of MDR1 or BCRP is predictive of tumor cell sensitivity to this agent, both in vitro and in vivo. The data provide a genetic basis for resistance to Aurora kinase inhibitors, which could be utilized to predict clinical response to therapy.