FLT3 Inhibitors in Acute Myeloid Leukemia: Current Status and Future Directions.
FLT3 Inhibitors in Acute Myeloid Leukemia: Current Status and Future Directions.
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DOI：
10.1158/1535-7163.mct-16-0876
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发表时间：
2017-06
影响因子：
5.7
通讯作者：
Baer MR
中科院分区：
文献类型：
--
作者：
Larrosa-Garcia M;Baer MR
受体酪氨酸激酶fms样酪氨酸激酶3（FLT 3）参与调节造血干/祖细胞的存活、增殖和分化，在大多数患者中表达于急性髓性白血病（AML）细胞上。导致组成性信号传导的FLT 3突变在AML中很常见，包括25%患者的质膜结构域中的内部串联重复（ITD）和5%患者的酪氨酸激酶结构域中的点突变。FLT 3-ITD AML患者在化疗和移植后的复发率高，无复发生存期和总生存期短。已经确定了许多FLT 3信号传导抑制剂，并正在进行临床试验，包括单独使用和与化疗联合使用，目的是改善FLT 3突变AML患者的临床结局。虽然抑制剂单药治疗产生临床反应，但它们通常是不完全和短暂的，并且耐药性迅速发展。已经提出了多种联合治疗以增强FLT 3抑制剂的疗效并防止耐药性的发展或克服耐药性。正在探索与表观遗传疗法、蛋白酶体抑制剂、下游激酶抑制剂、磷酸酶激活剂和其他改变信号传导的药物的组合。本文综述了FLT 3抑制剂在AML中的转化和临床研究现状，并讨论了新的联合治疗方法。
The receptor tyrosine kinase fms-like tyrosine kinase 3 (FLT3), involved in regulating survival, proliferation and differentiation of hematopoietic stem/progenitor cells, is expressed on acute myeloid leukemia (AML) cells in most patients. Mutations of FLT3 resulting in constitutive signaling are common in AML, including internal tandem duplication (ITD) in the juxtamembrane domain in 25% of patients and point mutations in the tyrosine kinase domain in 5%. Patients with AML with FLT3-ITD have a high relapse rate and short relapse-free and overall survival after chemotherapy and after transplant. A number of inhibitors of FLT3 signaling have been identified and are in clinical trials, both alone and with chemotherapy, with the goal of improving clinical outcomes in patients with AML with FLT3 mutations. While inhibitor monotherapy produces clinical responses, they are usually incomplete and transient, and resistance develops rapidly. Diverse combination therapies have been suggested to potentiate the efficacy of FLT3 inhibitors and to prevent development of resistance or overcome resistance. Combinations with epigenetic therapies, proteasome inhibitors, downstream kinase inhibitors, phosphatase activators and other drugs that alter signaling are being explored. This review summarizes the current status of translational and clinical research on FLT3 inhibitors in AML, and discusses novel combination approaches.