文章：

BRG1/BRM与FLT3抑制剂联合治疗对FLT3突变AML细胞的优异临床前疗效

Superior preclinical efficacy of co-treatment with BRG1/BRM and FLT3 inhibitor against AML cells with FLT3 mutations

原文发布日期：2025-03-15

DOI: 10.1038/s41408-025-01251-7

类型: Article

开放获取: 是

英文摘要：

Although treatment with standard frontline therapies, including a FLT3 inhibitor (FLT3i) reduces AML burden and achieves clinical remissions, most patients with AML with FLT3 mutation relapse due to therapy-resistant stem/progenitor cells. The core ATPases, BRG1 (SMARCA4) and BRM (SMARCA2) of the canonical (c) BAF (BRG1/BRM-associated factor) complex is a dependency in AML cells, including those harboring FLT3 mutations. We have previously reported that treatment with FHD-286, a BRG1/BRM ATPases inhibitor, induces differentiation and loss of viability of AML stem/progenitor cells. Findings of present studies demonstrate that treatment with FHD-286 induces lethality in AML cells, regardless of sensitivity or resistance to FLT3i. This efficacy is associated with the induction of gene-expression perturbations responsible for growth inhibition, differentiation, as well as a reduced AML-initiating potential of the AML cells. Additionally, co-treatment with FHD-286 and FLT3i exerts superior pre-clinical efficacy against AML cells and patient-derived (PD) xenograft (PDX) models of AML with FLT3 mutations.
 

摘要翻译： 

尽管采用包括FLT3抑制剂（FLT3i）在内的标准一线疗法治疗可减轻急性髓系白血病（AML）负荷并实现临床缓解，但大多数携带FLT3突变的AML患者仍因存在耐药性干细胞/祖细胞而复发。经典BAF复合体中的核心ATP酶——BRG1（SMARCA4）和BRM（SMARCA2），是AML细胞（包括携带FLT3突变细胞）生存的关键依赖因素。我们既往研究发现，BRG1/BRM ATP酶抑制剂FHD-286能够诱导AML干细胞/祖细胞分化并使其丧失活力。本研究结果表明，无论AML细胞对FLT3i敏感或耐药，FHD-286处理均能诱导其死亡。此效应与基因表达扰动相关，这些扰动会抑制细胞生长、促进分化，并降低AML细胞的疾病起始潜能。此外，FHD-286与FLT3i联用在临床前研究中表现出更优的抗白血病效果，该结论在携带FLT3突变的AML细胞及患者来源异种移植模型中均得到验证。

原文链接：

Superior preclinical efficacy of co-treatment with BRG1/BRM and FLT3 inhibitor against AML cells with FLT3 mutations