Knapper Steven
Department of Haematology, Cardiff University, Heath Park, Cardiff CF14 4XW, UK.
Br J Haematol. 2007 Sep;138(6):687-99. doi: 10.1111/j.1365-2141.2007.06700.x. Epub 2007 Jul 26.
FMS-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase that appears to play a significant role in leukaemogenesis. Activating mutations of FLT3 are present in approximately one-third of acute myeloid leukaemia patients and are associated with adverse clinical outcome, while many non-mutated cases also show evidence of FLT3 activation. FLT3 thus represents a potentially exciting molecular therapeutic target. A number of small-molecule tyrosine kinase inhibitors with anti-FLT3 activity have been developed and several of these compounds have entered early phase clinical trials where clinical anti-leukaemic activity has been demonstrated. The depth and duration of clinical responses to FLT3 inhibitor monotherapy have been modest, however, and a number of mechanisms by which blasts may acquire resistance have been proposed. Based on preclinical evidence of synergy with conventional chemotherapy, several combination trials are now underway. FLT3 inhibition may also be effective used in combination with other molecularly targeted agents, in postchemotherapy stem-cell-directed maintenance therapy and in MLL-rearranged infant acute lymphoblastic leukaemia.
FMS样酪氨酸激酶3（FLT3）是一种受体酪氨酸激酶，似乎在白血病发生过程中发挥重要作用。约三分之一的急性髓系白血病患者存在FLT3激活突变，且与不良临床预后相关，而许多未发生突变的病例也显示出FLT3激活的证据。因此，FLT3是一个潜在的令人兴奋的分子治疗靶点。已经开发出多种具有抗FLT3活性的小分子酪氨酸激酶抑制剂，其中几种化合物已进入早期临床试验阶段，并已证明具有临床抗白血病活性。然而，FLT3抑制剂单药治疗的临床反应深度和持续时间有限，并且已经提出了多种白血病细胞可能获得耐药性的机制。基于与传统化疗协同作用的临床前证据，目前正在进行多项联合试验。FLT3抑制与其他分子靶向药物联合使用、在化疗后干细胞定向维持治疗以及MLL重排的婴儿急性淋巴细胞白血病中也可能有效。
