Activity of a novel Aurora kinase inhibitor against the T315I mutant form of BCR-ABL:: In vitro and in vivo studies
Activity of a novel Aurora kinase inhibitor against the T315I mutant form of BCR-ABL:: In vitro and in vivo studies
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DOI：
10.1111/j.1349-7006.2008.00810.x
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发表时间：
2008-06-01
期刊：
影响因子：
5.7
通讯作者：
Ohyashiki, Kazuma
中科院分区：
文献类型：
--
作者：
Akahane, Daigo;Tauchi, Tetsuzo;Ohyashiki, Kazuma
尽管 ABL 激酶抑制剂的临床研究取得了有希望的结果，但仍然存在一个具有挑战性的问题，即 T315I 突变，尼洛替尼和达沙替尼均未表现出显着的活性。在本研究中，我们研究了一种新型极光激酶抑制剂 VE-465 对表达野生型 BCR-ABL 或 BCR-ABL T315I 突变形式的白血病细胞的活性。我们观察到 VE-465 处理的细胞中 BCR-ABL 自磷酸化水平呈剂量依赖性降低。暴露于 VE-465 和伊马替尼的组合可增强 K562 细胞的凋亡作用。 VE-465 和伊马替尼联合治疗导致 K562 细胞中磷酸 AKT 和 c-Myc 水平进一步减弱。此外，等效线图表明在 K562 细胞中同时暴露于 VE-465 和伊马替尼的协同效应。为了评估 VE-465 的体内功效，无胸腺裸鼠静脉注射表达野生型 BCR-ABL 或 T315I 突变型的 BaF3 细胞。接受载体治疗的小鼠在 28 天时死于类似急性白血病的病症；然而，几乎所有接受 VE-465（75 mg/kg，每天两次；腹腔注射 14 天）治疗的小鼠都存活了 56 天以上。对媒介物处理的小鼠的组织病理学分析显示脾脏浸润。相比之下，VE-465 治疗小鼠器官的组织病理学分析显示出正常的组织结构。综上所述，本研究表明 VE-465 表现出理想的治疗指数，可以有效地减少 T315I 突变型和野生型 BCR-ABL 表达细胞的体内生长。
Despite promising results from clinical studies of ABL kinase inhibitors, a challenging problem that remains is the T315I mutation against which neither nilotinib nor dasatinib show significant activity. In the present study, we investigated the activity of a novel Aurora kinase inhibitor, VE-465, against leukemia cells expressing wild-type BCR-ABL or the T315I mutant form of BCR-ABL. We observed a dose-dependent reduction in the level of BCR-ABL autophosphorylation in VE-465-treated cells. Exposure to the combination of VE-465 and imatinib exerted an enhanced apoptotic effect in K562 cells. Combined treatment with VE-465 and imatinib caused more attenuation of the levels of phospho-AKT and c-Myc in K562 cells. Further, the isobologram indicated the synergistic effect of simultaneous exposure to VE-465 and imatinib in K562 cells. To assess the in vivo efficacy of VE-465, athymic nude mice were injected intravenously with BaF3 cells expressing wild-type BCR-ABL or the T315I mutant form. The vehicle-treated mice died of a condition resembling acute leukemia by 28 days; however, nearly all mice treated with VE-465 (75 mg/kg, twice daily; intraperitoneally for 14 days) survived for more than 56 days. Histopathological analysis of vehicle-treated mice revealed infiltration of the spleen. In contrast, histopathological analysis of organs from VE-465-treated mice demonstrated normal tissue architecture. Taken together, the present study shows that VE-465 exhibits a desirable therapeutic index that can reduce the in vivo growth of T315I mutant form and wild-type BCR-ABL-expressing cells in an efficacious manner.