FLT3 Inhibitors in Acute Myeloid Leukemia: Current Status and Future Directions,Molecular Cancer Therapeutics

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FLT3 Inhibitors in Acute Myeloid Leukemia: Current Status and Future Directions
Molecular Cancer Therapeutics ( IF 5.3 ) Pub Date : 2017-06-01 , DOI: 10.1158/1535-7163.mct-16-0876
Maria Larrosa-Garcia ₁ , Maria R. Baer _{1,

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Affiliation

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. Mol Cancer Ther; 16(6); 991–1001. ©2017 AACR.

中文翻译：

急性髓系白血病中的 FLT3 抑制剂：现状和未来方向

受体酪氨酸激酶 fms 样酪氨酸激酶 3 (FLT3) 参与调节造血干/祖细胞的存活、增殖和分化，在大多数患者的急性髓系白血病 (AML) 细胞上表达。FLT3 突变导致组成型信号转导在 AML 中很常见，包括 25% 的患者近膜结构域的内部串联重复 (ITD) 和 5% 的酪氨酸激酶结构域的点突变。伴 FLT3-ITD 的 AML 患者在化疗和移植后复发率高，无复发和总生存期短。许多 FLT3 信号传导抑制剂已被确定并正在进行临床试验，无论是单独使用还是与化疗一起使用，目的是改善具有 FLT3 突变的 AML 患者的临床结果。虽然抑制剂单药治疗产生临床反应，但它们通常是不完整和短暂的，并且耐药性发展迅速。已建议采用多种联合疗法来增强 FLT3 抑制剂的功效并防止产生耐药性或克服耐药性。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的药物的组合。本综述总结了 FLT3 抑制剂在 AML 中的转化和临床研究的现状，并讨论了新的联合方法。摩尔癌症治疗; 16(6); 991-1001。©2017 AACR。已建议采用多种联合疗法来增强 FLT3 抑制剂的功效并防止产生耐药性或克服耐药性。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的药物的组合。本综述总结了 FLT3 抑制剂在 AML 中的转化和临床研究的现状，并讨论了新的联合方法。摩尔癌症治疗; 16(6); 991-1001。©2017 AACR。已建议采用多种联合疗法来增强 FLT3 抑制剂的功效并防止产生耐药性或克服耐药性。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的药物的组合。本综述总结了 FLT3 抑制剂在 AML 中的转化和临床研究的现状，并讨论了新的联合方法。摩尔癌症治疗; 16(6); 991-1001。©2017 AACR。本综述总结了 FLT3 抑制剂在 AML 中的转化和临床研究的现状，并讨论了新的联合方法。摩尔癌症治疗; 16(6); 991-1001。©2017 AACR。本综述总结了 FLT3 抑制剂在 AML 中的转化和临床研究的现状，并讨论了新的联合方法。摩尔癌症治疗; 16(6); 991-1001。©2017 AACR。

更新日期：2017-06-01

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