文章：

CUDC-907与gilteritinib联合在体外和体内均显示出对FLT3-ITD AML的良好抗白血病活性

The combination of CUDC-907 and gilteritinib shows promising in vitro and in vivo antileukemic activity against FLT3-ITD AML

原文发布日期：2021-06-07

DOI: 10.1038/s41408-021-00502-7

类型: Article

开放获取: 是

英文摘要：

About 25% of patients with acute myeloid leukemia (AML) harbor FMS-like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) mutations and their prognosis remains poor. Gilteritinib is a FLT3 inhibitor approved by the US FDA for use in adult FLT3-mutated relapsed or refractory AML patients. Monotherapy, while efficacious, shows short-lived responses, highlighting the need for combination therapies. Here we show that gilteritinib and CUDC-907, a dual inhibitor of PI3K and histone deacetylases, synergistically induce apoptosis in FLT3-ITD AML cell lines and primary patient samples and have striking in vivo efficacy. Upregulation of FLT3 and activation of ERK are mechanisms of resistance to gilteritinib, while activation of JAK2/STAT5 is a mechanism of resistance to CUDC-907. Gilteritinib and CUDC-907 reciprocally overcome these mechanisms of resistance. In addition, the combined treatment results in cooperative downregulation of cellular metabolites and persisting antileukemic effects. CUDC-907 plus gilteritinib shows synergistic antileukemic activity against FLT3-ITD AML in vitro and in vivo, demonstrating strong translational therapeutic potential.
 

摘要翻译： 

大约25%的急性髓系白血病（AML）患者携带FMS样酪氨酸激酶3（FLT3）内部串联重复（ITD）突变，其预后仍然较差。吉瑞替尼是一种FLT3抑制剂，已获美国FDA批准用于治疗成人FLT3突变复发或难治性AML患者。单药治疗虽有效，但缓解时间短暂，这凸显了联合疗法的必要性。本研究显示，吉瑞替尼与PI3K和组蛋白去乙酰化酶双重抑制剂CUDC-907可协同诱导FLT3-ITD AML细胞系及原代患者样本的细胞凋亡，并在体内表现出显著的抗白血病效果。FLT3上调与ERK激活是吉瑞替尼的耐药机制，而JAK2/STAT5激活是CUDC-907的耐药机制。吉瑞替尼与CUDC-907能够相互克服这些耐药机制。此外，联合治疗可协同下调细胞代谢物水平，并产生持续的抗白血病效应。CUDC-907联合吉瑞替尼在体外和体内均显示出对FLT3-ITD AML的协同抗白血病活性，具有明确的临床转化治疗潜力。

原文链接：

The combination of CUDC-907 and gilteritinib shows promising in vitro and in vivo antileukemic activity against FLT3-ITD AML