Prediction of resistance to small molecule FLT3 inhibitors: Implications for molecularly targeted therapy of acute leukemia
Prediction of resistance to small molecule FLT3 inhibitors: Implications for molecularly targeted therapy of acute leukemia
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DOI：
10.1158/0008-5472.can-04-2148
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发表时间：
2004-09-15
期刊：
影响因子：
11.2
通讯作者：
Gilliland, DG
中科院分区：
文献类型：
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作者：
Cools, J;Mentens, N;Gilliland, DG
受体酪氨酸激酶FLT 3的突变经常发生在急性髓细胞白血病（AML）和急性淋巴细胞白血病（ALL）患者中。选择性抑制FLT 3激酶活性的小分子可诱导AMI原始细胞、FLT 3突变患者的细胞凋亡，并延长FLT 3诱导的骨髓增生性疾病动物模型的生存期。已经描述了一系列具有抗FLT 3活性的结构不同的小分子，目前正在临床试验中研究其治疗AML和ALL的疗效。在这里，我们描述了一个体外筛选的结果，旨在确定突变的ATP结合口袋的FLT 3赋予耐药酪氨酸激酶抑制剂。鉴定了4个不同位置（Ala-627、Asn-676、Phe-691和Gly-697）的突变，这些突变赋予对PKC 412、SU 5614或K-252 a不同程度的抗性。在Ala-627、Asn-676或Phe-691处突变的FLT 3蛋白对较高浓度的抑制剂保持敏感，但G697 R突变赋予对这些抑制剂中的每一种以及对另外六种实验抑制剂的高水平抗性。这些数据提供了对FLT 3对小分子抑制剂获得性耐药的潜在机制的见解，并表明G697 R突变可能是一种临床上有问题的耐药突变，需要主动筛选其他抑制剂。
Mutations in the receptor tyrosine kinase FLT3 occur frequently in patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Small molecules that selectively inhibit FLT3 kinase activity induce apoptosis in blasts from AMI, patients with FLT3 mutations and prolong survival in animal models of FLT3-induced myeloproliferative disease. A spectrum of structurally different small molecules with activity against FLT3 have been described, and their efficacy for treatment of AML and ALL is now being investigated in clinical trials. Here, we describe the results of an in vitro screen designed to identify mutations in the ATP-binding pocket of FLT3 that confer resistance to tyrosine kinase inhibitors. Mutations at four different positions (Ala-627, Asn-676, Phe-691, and Gly-697) were identified that confer varying degrees of resistance to PKC412, SU5614, or K-252a. FLT3 proteins mutated at Ala-627, Asn-676, or Phe-691 remained sensitive to higher concentrations of the inhibitors, but the G697R mutation conferred high-level resistance to each of these inhibitors as well as to six additional experimental inhibitors. These data provide insights into potential mechanisms of acquired resistance of FLT3 to small molecule inhibitors and indicate that the G697R mutation may be a clinically problematic resistance mutation that warrants proactive screening for additional inhibitors.