Mutant FLT3:: A direct target of sorafenib in acute myelogenous leukemia
Mutant FLT3:: A direct target of sorafenib in acute myelogenous leukemia
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DOI：
10.1093/jnci/djm328
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发表时间：
2008-02-06
影响因子：
10.3
通讯作者：
Andreeff, Michael
中科院分区：
文献类型：
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作者：
Zhang, Weiguo;Konopleva, Marina;Andreeff, Michael
研究背景在30%的急性髓系白血病（AML）患者中发现了Fms样酪氨酸激酶3（FLT 3）基因跨膜结构域编码序列的内部串联重复（ITD）突变，该突变与不良预后相关。激酶抑制剂索拉非尼诱导FLT 3-ITD突变的AML细胞系生长停滞和凋亡的浓度远低于野生型FLT 3的AML细胞系。在一个实施方案中，在原代人AML细胞中和在小鼠白血病异种移植物模型中观察人FLT 3（ITD、D835 G和D835 Y）或野生型人FLT 3的表达。分别通过流式细胞术和免疫印迹分析研究索拉非尼对AML细胞系中细胞凋亡和信号传导的影响，并通过监测用索拉非尼治疗的携带白血病异种移植物的小鼠（15只小鼠的组）的存活来确定体内效应。在1期临床试验中，16例难治性或复发性AML患者接受了索拉非尼不同剂量方案的治疗。我们通过聚合酶链反应测定确定了他们的FLT 3突变状态，并通过标准标准分析了临床反应。结果索拉非尼诱导FLT 3-ITD或D835 G突变的Ba/F3细胞生长停滞和凋亡的有效性是FLT 3-D835 Y突变或野生型FLT 3的1000- 3000倍，并抑制ITD突变蛋白酪氨酸残基的磷酸化，但不抑制野生型FLT 3蛋白。在小鼠模型中，索拉非尼降低了白血病负荷并延长了生存期（索拉非尼治疗组与溶媒治疗组的中位生存期= 36.5 vs 16天，差异= 20.5天，95%置信区间= 20.3 - 21.3天; P = 0.0018）。索拉非尼降低FLT 3-ITD AML患者外周血和骨髓中白血病原始细胞的百分比（索拉非尼治疗前后的中位数百分比：81% vs 7.5% [P = .016]和75.5% vs 34% [P = .05]，结论索拉非尼可能对FLT 3基因突变的AML患者有治疗作用。ITD突变。
Background Internal tandem duplication (ITD) mutations in the juxtamembrane domain-coding sequence of the Fms-like tyrosine kinase 3 (FLT3) gene have been identified in 30% of acute myeloid leukemia (AML) patients and are associated with a poor prognosis. The kinase inhibitor sorafenib induces growth arrest and apoptosis at much lower concentrations in AML cell lines that harbor FLT3-ITD mutations than in AML cell lines with wild-type FLT3.Methods The antileukemic activity of sorafenib was investigated in isogenic murine Ba/F3 AML cell lines that expressed mutant (ITD, D835G, and D835Y) or wild-type human FLT3, in primary human AML cells, and in a mouse leukemia xenograft model. Effects of sorafenib on apoptosis and signaling in AML cell lines were investigated by flow cytometry and immunoblot analysis, respectively, and the in vivo effects were determined by monitoring the survival of leukemia xenograft-bearing mice treated with sorafenib (groups of 15 mice). In a phase 1 clinical trial, 16 patients with refractory or relapsed AML were treated with sorafenib on different dose schedules. We determined their FLT3 mutation status by a polymerase chain reaction assay and analyzed clinical responses by standard criteria. All statistical tests were two-sided.Results Sorafenib was 1000- to 3000- fold more effective in inducing growth arrest and apoptosis in Ba/F3 cells with FLT3-ITD or D835G mutations than in Ba/F3 cells with FLT3-D835Y mutant or wild-type FLT3 and inhibited the phosphorylation of tyrosine residues in ITD mutant but not wild-type FLT3 protein. In a mouse model, sorafenib decreased the leukemia burden and prolonged survival ( median survival in the sorafenib-treated group vs the vehicle-treated group = 36.5 vs 16 days, difference = 20.5 days, 95% confidence interval = 20.3 to 21.3 days; P =.0018). Sorafenib reduced the percentage of leukemia blasts in the peripheral blood and the bone marrow of AML patients with FLT3-ITD (median percentages before and after sorafenib: 81% vs 7.5% [P = .016] and 75.5% vs 34% [P = .05], respectively) but not in patients without this mutation.Conclusion Sorafenib may have therapeutic efficacy in AML patients whose cells harbor FLT3-ITD mutations.