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Ref Type Journal Article
PMID (38437498)
Authors Fiskus W, Piel J, Collins MP, Hentemann M, Cuglievan B, Mill CP, Birdwell C, Das K, Davis JA, Hou H, Jain A, Malovannaya A, Kadia TM, Daver NG, Sasaki K, Takahashi K, Hammond D, Reville PK, Wang J, Loghavi S, Sen R, Ruan X, Su X, Flores L, DiNardo CD, Bhalla KN
Title BRG1/BRM inhibitor targets AML stem cells and exerts superior preclinical efficacy combined with BET or Menin inhibitor.
Journal Vol Issue Date Pages Journal Short Title
Blood 2024 Feb 16 Blood
URL
Abstract Text 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/co-factors to access enhancers/promoter and modulate gene-expressions responsible for cell growth and differentiation of AML stem/progenitor cells. In AML with MLL1r (MLL1 rearrangement) or mutant (mt) NPM1, 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. Co-treatment 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 patient-derived xenograft (PDX) models of AML with MLL1r or mtNPM1, FHD-286 treatment reduced AML burden, improved survival, and attenuated AML-initiating potential of stem-progenitor cells. Compared to each drug, co-treatment 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 promising therapy of AML with MLL1r or mtNPM1.

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