The University of Texas MD Anderson Cancer Center, Houston, TX.
Foghorn Therapeutics, Cambridge, MA.
Blood. 2024 May 16;143(20):2059-2072. doi: 10.1182/blood.2023022832.
BRG1 (SMARCA4) and BRM (SMARCA2) are the mutually exclusive core ATPases of the chromatin remodeling BAF (BRG1/BRM-associated factor) complexes. They enable transcription factors/cofactors to access enhancers/promoter and modulate gene expressions responsible for cell growth and differentiation of acute myeloid leukemia (AML) stem/progenitor cells. In AML with MLL1 rearrangement (MLL1r) or mutant NPM1 (mtNPM1), although menin inhibitor (MI) treatment induces clinical remissions, most patients either fail to respond or relapse, some harboring menin mutations. FHD-286 is an orally bioavailable, selective inhibitor of BRG1/BRM under clinical development in AML. Present studies show that FHD-286 induces differentiation and lethality in AML cells with MLL1r or mtNPM1, concomitantly causing perturbed chromatin accessibility and repression of c-Myc, PU.1, and CDK4/6. Cotreatment with FHD-286 and decitabine, BET inhibitor (BETi) or MI, or venetoclax synergistically induced in vitro lethality in AML cells with MLL1r or mtNPM1. In models of xenografts derived from patients with AML with MLL1r or mtNPM1, FHD-286 treatment reduced AML burden, improved survival, and attenuated AML-initiating potential of stem-progenitor cells. Compared with each drug, cotreatment with FHD-286 and BETi, MI, decitabine, or venetoclax significantly reduced AML burden and improved survival, without inducing significant toxicity. These findings highlight the FHD-286-based combinations as a promising therapy for AML with MLL1r or mtNPM1.
BRG1（SMARCA4）和 BRM（SMARCA2）是染色质重塑 BAF（BRG1/BRM 相关因子）复合物中相互排斥的核心 ATP 酶。它们使转录因子/辅因子能够接近增强子/启动子，并调节负责急性髓系白血病（AML）干细胞/祖细胞生长和分化的基因表达。在具有 MLL1 重排（MLL1r）或突变型 NPM1（mtNPM1）的 AML 中，尽管 menin 抑制剂（MI）治疗可诱导临床缓解，但大多数患者要么没有反应，要么复发，有些患者存在 menin 突变。FHD-286 是一种在 AML 中临床开发的 BRG1/BRM 的口服生物可利用的选择性抑制剂。目前的研究表明，FHD-286 可诱导具有 MLL1r 或 mtNPM1 的 AML 细胞分化和致死，同时导致染色质可及性紊乱和 c-Myc、PU.1 和 CDK4/6 的抑制。FHD-286 与地西他滨、BET 抑制剂（BETi）或 MI 或 venetoclax 联合治疗可协同诱导具有 MLL1r 或 mtNPM1 的 AML 细胞体外致死。在源自具有 MLL1r 或 mtNPM1 的 AML 患者的异种移植模型中，FHD-286 治疗可降低 AML 负担、改善生存并减弱干细胞/祖细胞的 AML 起始潜能。与每种药物相比，FHD-286 与 BETi、MI、地西他滨或 venetoclax 联合治疗可显著降低 AML 负担并改善生存，而不会引起明显的毒性。这些发现强调了基于 FHD-286 的联合治疗作为具有 MLL1r 或 mtNPM1 的 AML 的一种有前途的治疗方法。
