Fiskus Warren, Mill Christopher P, Piel Jessica, Collins Mike, Hentemann Murphy, Cuglievan Branko, Birdwell Christine E, Das Kaberi, Hou Hanxi, Davis John A, Jain Antrix, Malovannaya Anna, Kadia Tapan M, Daver Naval, Sasaki Koji, Takahashi Koichi, Hammond Danielle, Reville Patrick K, Flores Lauren B, Loghavi Sanam, Su Xiaoping, DiNardo Courtney D, Bhalla Kapil N
The University of Texas M.D. Anderson Cancer Center, Houston, TX, 77030, USA.
Foghorn Therapeutics, Cambridge, MA, 02139, USA.
Blood Cancer J. 2025 Mar 15;15(1):40. doi: 10.1038/s41408-025-01251-7.
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.
尽管采用包括FLT3抑制剂（FLT3i）在内的标准一线疗法进行治疗可减轻急性髓系白血病（AML）负担并实现临床缓解，但大多数伴有FLT3突变的AML患者会因治疗耐药的干细胞/祖细胞而复发。经典（c）BAF（BRG1/BRM相关因子）复合物的核心ATP酶BRG1（SMARCA4）和BRM（SMARCA2）是AML细胞（包括那些携带FLT3突变的细胞）的一个依赖性因素。我们之前报道过，使用BRG1/BRM ATP酶抑制剂FHD-286进行治疗可诱导AML干细胞/祖细胞分化并丧失活力。目前研究的结果表明，无论对FLT3i敏感或耐药，使用FHD-286进行治疗均可诱导AML细胞死亡。这种疗效与诱导导致生长抑制、分化的基因表达扰动以及降低AML细胞的白血病起始潜能有关。此外，FHD-286与FLT3i联合治疗对AML细胞以及伴有FLT3突变的AML患者来源（PD）异种移植（PDX）模型具有卓越的临床前疗效。
