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.

大约 25% 的急性髓性白血病 (AML) 患者存在 FMS 样酪氨酸激酶 3 (FLT3) 内部串联重复 (ITD) 突变，其预后仍然很差。Gilteritinib 是美国 FDA 批准的 FLT3 抑制剂，用于成人 FLT3 突变的复发或难治性 AML 患者。单一疗法虽然有效，但反应短暂，突出了联合疗法的必要性。在这里，我们显示 gilteritinib 和 CUDC-907（一种 PI3K 和组蛋白去乙酰化酶的双重抑制剂）在 FLT3-ITD AML 细胞系和原发性患者样本中协同诱导细胞凋亡，并具有显着的体内疗效。FLT3 的上调和 ERK 的激活是对 gilteritinib 耐药的机制，而 JAK2/STAT5 的激活是对 CUDC-907 耐药的机制。Gilteritinib 和 CUDC-907 相互克服了这些耐药机制。此外，联合治疗导致细胞代谢物的协同下调和持续的抗白血病作用。CUDC-907 加 gilteritinib 在体外和体内对 FLT3-ITD AML 显示出协同抗白血病活性，显示出强大的转化治疗潜力。