Department of Academic Haematology, University of Nottingham, Nottingham, United Kingdom.
Mol Cancer Ther. 2010 Mar;9(3):661-72. doi: 10.1158/1535-7163.MCT-09-1144. Epub 2010 Feb 16.
Aurora kinases play an essential role in orchestrating chromosome alignment, segregation, and cytokinesis during mitotic progression and both aurora-A and B are frequently overexpressed in a variety of human malignancies. In this study, we report the effects of AZD1152-HQPA, a highly selective inhibitor of aurora-B kinase, in acute myeloid leukemia (AML) cell lines and primary samples. We show that AZD1152-HQPA inhibits the phosphorylation of Histone H3 (pHH3) on serine 10 resulting in polyploid cells, apoptosis, and loss of viability in a panel of AML cell lines. We also show that AZD1152-HQPA sensitivity in our cell lines is irrespective of p53 status and the FLT3-ITD-expressing MOLM-13 and MV4-11 cell lines are particularly sensitive to AZD1152-HQPA. Internal tandem duplications (ITD) within the FLT3 tyrosine kinase receptor are found in approximately 25% of AML patients and are associated with a poor prognosis. Here, we report that AZD1152-HQPA directly targets phosphorylated FLT3 along with inhibiting its downstream target phospho-signal transducer and activator of transcription 5 (STAT5) in the FLT3-ITD cell lines. We show pHH3 expression in primary AML blasts and its inhibition by AZD1152-HQPA at low doses in all of our primary samples tested. AZD1152-HQPA inhibits the clonogenic potential of primary AML samples, with FLT3-ITD samples being the most sensitive (P = 0.029). FLT3-ITD primary samples are also more sensitive to pHH3 inhibition (P = 0.022) and are particularly sensitive to pSTAT5 downregulation after treatment with AZD1152-HQPA compared with FLT3 wild-type samples (P = 0.007). We conclude that mutant FLT3 is a secondary target of AZD1152-HQPA and that FLT3-ITD primary samples are particularly sensitive to the drug.
极光激酶在有丝分裂过程中对染色体的排列、分离和胞质分裂起着至关重要的作用，极光-A 和极光-B 在多种人类恶性肿瘤中经常过表达。在这项研究中，我们报告了 Aurora-B 激酶的高度选择性抑制剂 AZD1152-HQPA 在急性髓细胞白血病（AML）细胞系和原代样本中的作用。我们表明，AZD1152-HQPA 抑制组蛋白 H3（pHH3）丝氨酸 10 的磷酸化，导致多倍体细胞、细胞凋亡和细胞活力丧失在一系列 AML 细胞系中。我们还表明，我们的细胞系对 AZD1152-HQPA 的敏感性与 p53 状态无关，并且表达 FLT3-ITD 的 MOLM-13 和 MV4-11 细胞系对 AZD1152-HQPA 特别敏感。FLT3 酪氨酸激酶受体内部串联重复（ITD）约见于 25%的 AML 患者，与预后不良相关。在这里，我们报告 AZD1152-HQPA 直接靶向磷酸化的 FLT3，同时抑制其下游靶标磷酸信号转导和转录激活物 5（STAT5）在 FLT3-ITD 细胞系中。我们在所有测试的原代 AML 样本中均显示 pHH3 的表达，并在低剂量下显示其被 AZD1152-HQPA 抑制。AZD1152-HQPA 抑制原代 AML 样本的集落形成能力，其中 FLT3-ITD 样本最为敏感（P=0.029）。FLT3-ITD 原代样本对 pHH3 抑制也更敏感（P=0.022），与 FLT3 野生型样本相比，经 AZD1152-HQPA 治疗后，pSTAT5 下调更为敏感（P=0.007）。我们得出结论，突变型 FLT3 是 AZD1152-HQPA 的次要靶点，FLT3-ITD 原代样本对该药物特别敏感。
