FLT3 inhibitors for acute myeloid leukemia: a review of their efficacy and mechanisms of resistance
FLT3 inhibitors for acute myeloid leukemia: a review of their efficacy and mechanisms of resistance
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DOI：
10.1007/s12185-013-1334-8
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发表时间：
2013-06-01
影响因子：
2.1
通讯作者：
Levis, Mark J.
中科院分区：
文献类型：
--
作者：
Grunwald, Michael R.;Levis, Mark J.
自从2001年美国食品和药物管理局批准伊马替尼用于治疗慢性粒细胞白血病以来，酪氨酸激酶抑制剂(TKIs)已成为许多恶性肿瘤的主要治疗药物。在急性髓系白血病(AML)中，FMS样酪氨酸激酶3(Flt3)基因的激活突变会导致白血病原始细胞的存活和增殖，并与不良预后相关。因此，Flt3受体是一个有吸引力的抑制靶点。目前，针对Flt3突变的AML正在开发多种小分子TKI，药物开始显示出良好的疗效。在其他恶性肿瘤中，在治疗过程中对TKI的耐药性的产生已被证明是一个挑战，到目前为止，在Flt3 TKIs的临床试验中，对抑制的耐药性是成功抑制Flt3的一个重要障碍。了解耐药性的机制并克服这些阻碍靶向抑制的因素将是这些药物成功的关键。
Since the Food and Drug Administration approval of imatinib for treatment of chronic myeloid leukemia in 2001, tyrosine kinase inhibitors (TKIs) have become a mainstay in the care of many malignancies. In acute myeloid leukemia (AML), activating mutations in the FMS-like tyrosine kinase 3 (FLT3) gene result in survival and proliferation of leukemic blasts and are associated with adverse prognosis. Therefore, the FLT3 receptor is an appealing target for inhibition. Multiple small molecule TKIs are currently in development for FLT3-mutated AML, and agents are beginning to show promising efficacy. In other malignancies, the development of resistance to TKIs during the course of therapy has proven to be a challenge, and thus far, in clinical trials of FLT3 TKIs, resistance to inhibition represents a significant barrier to successful FLT3 inhibition. Understanding the mechanisms of resistance and overcoming these obstacles to target inhibition will be central to the success of these agents.