A FLT3-targeted tyrosine kinase inhibitor is cytotoxic to leukemia cells in vitro and in vivo
A FLT3-targeted tyrosine kinase inhibitor is cytotoxic to leukemia cells in vitro and in vivo
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DOI：
10.1182/blood.v99.11.3885
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发表时间：
2002-06-01
期刊：
影响因子：
20.3
通讯作者：
Small, D
中科院分区：
文献类型：
--
作者：
Levis, M;Allebach, J;Small, D
高达41%的急性髓性白血病（AML）患者存在酪氨酸激酶FLT3受体组成性激活的内部串联重复（ITD）和点突变。这些FLT3/ITD突变可能很重要，因为它们的存在与预后不良有关。两种类型的突变似乎都激活了FLT3的酪氨酸激酶活性。我们在这里描述了吲哚咔唑衍生物CEP-701作为FLT3抑制剂的鉴定和表征。该药物在体外FLT3/ itd转染细胞和表达FLT3的人髓系白血病来源细胞系中，有效地选择性地抑制野生型和组成型激活突变FLT3的自磷酸化。我们证明CEP-701以剂量响应的方式诱导细胞毒性作用，与FLT3的抑制相似。FLT3信号通路中的下游靶点STAT5和ERK1/2在FLT3抑制的情况下受到抑制。在携带FLT3/ITD突变的AML患者的原发性白血病胚中，FLT3也受到抑制，并伴有相关的细胞毒性反应。最后，通过FLT3/ITD白血病小鼠模型，我们证明了该药物在体内抑制FLT3磷酸化并延长生存期。这些发现为CEP-701在携带flt3激活突变的AML患者中的计划临床试验奠定了基础。(C) 2002年由美国血液病学会出版。
Constitutively activating internal tandem duplication (ITD) and point mutations of the receptor tyrosine kinase FLT3 are present in up to 41% of patients with acute myeloid leukemia (AML). These FLT3/ITD mutations are likely to be important because their presence is associated with a poor prognosis. Both types of mutations appear to activate the tyrosine kinase activity of FLT3. We describe here the identification and characterization of the Indolocarbazole derivative CEP-701 as a FLT3 inhibitor. This drug potently and selectively inhibits autophosphorylation of wild-type and constitutively activated mutant FLT3 in vitro in FLT3/ITD-transfected cells and in human FLT3-expressing myeloid leukemia-derived cell lines. We demonstrate that CEP-701 induces a cytotoxic effect on cells in a dose-responsive fashion that parallels the inhibition of FLT3. STAT5 and ERK1/2, downstream targets of FLT3 in the signaling pathway, are inhibited in response to FLT3 inhibition. In primary leukemia blasts from AML patients harboring FLT3/ITD mutations, FLT3 is also inhibited, with an associated cytotoxic response. Finally, using a mouse model of FLT3/ITD leukemia, we demonstrate that the drug inhibits FLT3 phosphorylation in vivo and prolongs survival. These findings form the basis for a planned clinical trial of CEP-701 in patients with AML harboring FLT3-activating mutations. (C) 2002 by The American Society of Hematology.