Guo J, Anderson M G, Tapang P, Palma J P, Rodriguez L E, Niquette A, Li J, Bouska J J, Wang G, Semizarov D, Albert D H, Donawho C K, Glaser K B, Shah O J
Cancer Biology, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064-6121, USA.
Pharmacogenomics J. 2009 Apr;9(2):90-102. doi: 10.1038/tpj.2008.20. Epub 2009 Feb 3.
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.
AZD1152是一种高度选择性的极光激酶B抑制剂，目前正在对急性髓性白血病和晚期实体恶性肿瘤患者进行I期和II期临床评估。我们从SW620结肠癌细胞系和MiaPaCa胰腺癌细胞系中建立了两种对AZD1152耐药的细胞系，它们对AZD1152的活性代谢产物AZD1152 HQPA具有超过100倍的耐药性，有趣的是，对泛极光激酶抑制剂VX-680/MK0457也具有交叉耐药性。通过全基因组微阵列分析和比较基因组杂交，我们能够确定MDR1和BCRP是这些模型中AZD1152 HQPA耐药性的致病基因。此外，这两个基因中任何一个的上调都足以使体内肿瘤生长对AZD1152不敏感。最后，MDR1或BCRP的上调可预测肿瘤细胞在体外和体内对该药物的敏感性。这些数据为极光激酶抑制剂耐药性提供了遗传基础，可用于预测临床治疗反应。
