Activity of the Aurora kinase inhibitor VX-680 against Bcr/Abl-positive acute lymphoblastic leukemias.
Activity of the Aurora kinase inhibitor VX-680 against Bcr/Abl-positive acute lymphoblastic leukemias.
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DOI：
10.1158/1535-7163.mct-10-0069
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发表时间：
2010-05
影响因子：
5.7
通讯作者：
Heisterkamp N
中科院分区：
文献类型：
--
作者：
Fei F;Stoddart S;Groffen J;Heisterkamp N
对于费城染色体阳性（Ph 阳性）急性淋巴细胞白血病（ALL）患者来说，由于 Bcr/Abl 点突变而出现对酪氨酸激酶抑制剂的耐药性是一个具有挑战性的问题，特别是对于那些具有 T315I 突变的患者，尼洛替尼和达沙替尼均未显示出显着的活性。 VX-680 是一种泛极光激酶抑制剂，对所有 Bcr/Abl 蛋白均具有活性，但尚未在 Ph 阳性 ALL 的临床前模型中进行广泛检查。在这里，我们测试了 VX-680 在白血病细胞受到基质保护时治疗 Bcr/Abl 阳性 ALL 的效果。在这些条件下，VX-680 对具有或不具有 T315I 突变的原代人 Ph 阳性 ALL 细胞显示出显着影响，包括消除 Bcr/Abl 下游的酪氨酸磷酸化、降低活力和诱导细胞凋亡。然而，对人 Ph 阳性 ALL 细胞进行 3 天药物处理，然后去除药物，21 天后异常细胞就会生长出来，而在具有较低浓度 VX-680 的基质上培养小鼠 Bcr/Abl ALL 细胞时，出现了耐药细胞。使用 VX-680 和达沙替尼联合治疗缺乏 T315I 突变的人类 ALL 细胞，比单独使用每种药物产生显着更高的细胞毒性。我们建议，使用 VX-680 与第二种有效药物作为 Ph 阳性 ALL 的一线治疗可能比 VX-680 作为耐药 T315I Ph 阳性 ALL 单一疗法的二线治疗更安全、更有用。
The emergence of resistance to tyrosine kinase inhibitors due to point mutations in Bcr/Abl is a challenging problem for Philadelphia-chromosome positive (Ph-positive) acute lymphoblastic leukemia (ALL) patients, especially for those with the T315I mutation, against which neither nilotinib or dasatinib shows significant activity. VX-680 is a pan-Aurora kinase inhibitor active against all Bcr/Abl proteins but has not been extensively examined in preclinical models of Ph-positive ALL. Here, we have tested VX-680 for treatment of Bcr/Abl positive ALL when leukemic cells are protected by the presence of stroma. Under these conditions, VX-680 showed significant effects on primary human Ph-positive ALL cells both with and without the T315I mutation, including ablation of tyrosine phosphorylation downstream of Bcr/Abl, decreased viability and induction of apoptosis. However, drug treatment of human Ph-positive ALL cells for 3 days followed by drug removal allowed the outgrowth of abnormal cells 21 days later, and upon culture of mouse Bcr/Abl ALL cells on stroma with lower concentrations of VX-680, drug-resistant cells emerged. Combined treatment of human ALL cells lacking the T315I mutation with both VX-680 and dasatinib caused significantly more cytotoxicity than each drug alone. We suggest that use of VX-680 together with a second effective drug as first-line treatment for Ph-positive ALL is likely to be safer and more useful than second-line treatment with VX-680 as monotherapy for drug-resistant T315I Ph-positive ALL.