Uniform sensitivity of FLT3 activation loop mutants to the tyrosine kinase inhibitor midostaurin
Uniform sensitivity of FLT3 activation loop mutants to the tyrosine kinase inhibitor midostaurin
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DOI：
10.1182/blood-2007-07-101238
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发表时间：
2007-12-15
期刊：
影响因子：
20.3
通讯作者：
Gilliland, D. Gary
中科院分区：
文献类型：
--
作者：
Barry, Elly V.;Clark, Jennifer J.;Gilliland, D. Gary
靶向fms样酪氨酸激酶3（FLT 3）激活突变的小分子抑制剂在白血病治疗中具有潜力。然而，某些突变可以同时激活酪氨酸激酶，并赋予对小分子抑制剂的抗性。因此，我们测试了8个FILT 3激活环突变体对米多鲁肽的敏感性。每个突变体赋予Ba/F3细胞IL-3因子非依赖性增殖，并且每个突变体导致FLT 3及其靶点、信号转导和转录激活因子5（STAT 5）和细胞外刺激应答激酶（ERK）的组成性激活。对于每种测试的突变体，米多替林抑制细胞生长和FILT 3、STAT 5和ERK的磷酸化。相比之下，米多他鲁因不抑制稳定转导有FLT 3-内部串联重复的Ba/F3细胞，所述FLT 3-内部串联重复含有G697 R突变，所述G697 R突变赋予米多他鲁因抗性，这证明米多他鲁因抑制FILT 3激活环突变体不是由于脱靶效应。我们的结论是，米多鲁肽是一个有效的抑制剂的频谱FLT 3激活环突变，急性髓细胞白血病患者与这些突变是潜在的候选人涉及米多鲁肽的临床试验。
Small molecule inhibitors that target fms-like tyrosine kinase 3 (FLT3)-activating mutations have potential in the treatment of leukemias. However, certain mutations can simultaneously activate the tyrosine kinase, and confer resistance to small molecule inhibitors. We therefore tested the sensitivity of 8 FILT3 activation loop mutants to midostaurin. Each mutant conferred IL-3 factor-independent proliferation to Ba/F3 cells, and each resulted in the constitutive activation of FLT3 and its targets, signal transducer and activator of transcription 5 (STAT5) and extracellular stimuli-responsive kinase (ERK). For each mutant tested, midostaurin inhibited cell growth and phosphorylation of FILT3, STAT5, and ERK. In contrast, midostaruin did not inhibit Ba/F3 cells stably transduced with FLT3-internal tandem duplications containing a G697R mutation that confers resistance to midostaurin, demonstrating that midostaurin inhibition of FILT3 activation loop mutants was not due to off-target effects. We conclude that midostaurin is a potent inhibitor of a spectrum of FLT3 activation loop mutations, and that acute myeloid leukemia patients with such mutations are potential candidates for clinical trials involving midostaurin.