Overcoming AC220 resistance of FLT3-ITD by SAR302503.
Overcoming AC220 resistance of FLT3-ITD by SAR302503.
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DOI：
10.1038/bcj.2013.40
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发表时间：
2013-08-30
影响因子：
12.8
通讯作者：
Azam, M.
中科院分区：
文献类型：
--
作者：
Kesarwani, M.;Huber, E.;Azam, M.
通过内部串联重复（ITD）突变激活FLT3 （fms样酪氨酸激酶3）突变在大约30%的急性髓性白血病（AML）患者中发现，并且与该患者群体的不良预后相关。许多FLT3抑制剂已被测试用于治疗AML，但这些抑制剂显示出不同的反应，这归因于AML的异质性和与这些抑制剂所采用的抑制机制相关的机制差异。然而，许多患者显示出原始细胞计数减少和血液学改善，但这些缓解并不持久，这质疑了FLT3作为AML治疗靶点的有效性。为了解决这个问题，Neil Shah的团队设计了一项优雅的转化研究，在所有FLT3-ITD复发患者中发现了AC220耐药突变，明确证明了FLT3-ITD作为人类AML治疗靶点的有效性。此外，据报道，在接受pkc4123和索拉非尼治疗的FLT3-ITD复发AML患者中出现了耐药突变。此外，体外耐药筛选鉴定出gatekeeper残基突变，赋予对所有已知FLT3抑制剂的交叉耐药。这些观察结果表明，在激酶结构域产生耐药的继发性突变将构成重大的临床挑战，这促使我们寻找针对FLT3耐药变体的新抑制剂。
Activating mutations in FLT3 (Fms-like tyrosine kinase 3) by internal tandem duplication (ITD) mutations are found in approximately 30% of patients with acute myeloid leukemia (AML) and are associated with poor outcome in this patient population. Numerous FLT3 inhibitors have been tested for the treatment of AML, but these inhibitors have shown variable responses that were attributed to heterogeneity in AML and mechanistic differences associated with inhibitory mechanism employed by these inhibitors. 1 Nevertheless, many patients showed a reduction in blast counts and hematological improvements, but these remissions were not durable that questioned the validity of FLT3 as a therapeutic target in AML. To address this, an elegant translational study designed by Neil Shah’s group has identified the AC220 resistant mutations in all FLT3-ITD relapsed patients that definitively demonstrated the validity of FLT3-ITD as a therapeutic target in human AML. 2 Furthermore, the emergence of resistant mutations has been reported from the relapsed AML patients with FLT3-ITD treated with PKC412 3 and sorafenib. 4 In addition, an in vitro resistant screening identified mutation at gatekeeper residue conferred cross-resistance to all known FLT3 inhibitors. 5 These observations suggest that secondary mutations conferring resistance in the kinase domain will pose a significant clinical challenge, which prompted us to identify new inhibitors against the FLT3 resistant variants.
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