GlaxoSmithKline Oncology Research, Cancer Metabolism, 1250 Collegeville Road, Collegeville, PA 19426, USA.
J Transl Med. 2011 Jul 15;9:110. doi: 10.1186/1479-5876-9-110.
Aurora kinases play critical roles in mitosis and are being evaluated as therapeutic targets in cancer. GSK1070916 is a potent, selective, ATP competitive inhibitor of Aurora kinase B and C. Translation of predictive biomarkers to the clinic can benefit patients by identifying the tumors that are more likely to respond to therapies, especially novel inhibitors such as GSK1070916.
59 Hematological cancer-derived cell lines were used as models for response where in vitro sensitivity to GSK1070916 was based on both time and degree of cell death. The response data was analyzed along with karyotype, transcriptomics and somatic mutation profiles to determine predictors of response.
20 cell lines were sensitive and 39 were resistant to treatment with GSK1070916. High chromosome number was more prevalent in resistant cell lines (p-value = 0.0098, Fisher Exact Test). Greater resistance was also found in cell lines harboring polyploid subpopulations (p-value = 0.00014, Unpaired t-test). A review of NOTCH1 mutations in T-ALL cell lines showed an association between NOTCH1 mutation status and chromosome number (p-value = 0.0066, Fisher Exact Test).
High chromosome number associated with resistance to the inhibition of Aurora B and C suggests cells with a mechanism to bypass the high ploidy checkpoint are resistant to GSK1070916. High chromosome number, a hallmark trait of many late stage hematological malignancies, varies in prevalence among hematological malignancy subtypes. The high frequency and relative ease of measurement make high chromosome number a viable negative predictive marker for GSK1070916.
极光激酶在有丝分裂中发挥着关键作用，目前正在作为癌症治疗靶点进行评估。GSK1070916 是一种强效、选择性、ATP 竞争性的 Aurora 激酶 B 和 C 的抑制剂。将预测性生物标志物转化为临床应用可以使患者受益，因为它可以识别出更有可能对治疗产生反应的肿瘤，尤其是新型抑制剂如 GSK1070916。
使用 59 种血液系统癌症衍生细胞系作为模型来评估反应，这些模型的体外对 GSK1070916 的敏感性基于细胞死亡的时间和程度。对这些反应数据进行分析，并结合细胞遗传学、转录组学和体细胞突变谱，以确定反应的预测因子。
有 20 个细胞系对 GSK1070916 治疗敏感，39 个细胞系耐药。耐药细胞系中高染色体数更为常见（p 值=0.0098，Fisher 精确检验）。在含有多倍体亚群的细胞系中，也发现了更高的耐药性（p 值=0.00014，未配对 t 检验）。对 T-ALL 细胞系中 NOTCH1 突变的回顾显示，NOTCH1 突变状态与染色体数之间存在关联（p 值=0.0066，Fisher 精确检验）。
高染色体数与 Aurora B 和 C 抑制的耐药性相关，表明具有绕过高倍体检查点机制的细胞对 GSK1070916 耐药。高染色体数是许多晚期血液恶性肿瘤的标志特征，在血液恶性肿瘤亚型中的发生率存在差异。高染色体数的高频率和相对易于测量使其成为 GSK1070916 的可行阴性预测标志物。
