Abstract 451: Superior preclinical efficacy of BRG1/BRM inhibitor combined with BET inhibitor or decitabine against MECOM-rearranged AML
Authors: Warren C. Fiskus, Christopher P. Mill, Jessica Piel, Murphy Hentemann, Christine E. Birdwell, Kaberi Das, Hanxi Hou, John A. Davis, Surbhi Sharma, Tapan M. Kadia, Naval Daver, Sanam Loghavi, Courtney D. DiNardo, Kapil N. Bhalla
Journal: Cancer Research (2025)

Abstract AML with MECOM rearrangement (r) involving chromosome 3q26.2, specifically inv(3)(q21q26.2) or a translocation t(3;3)(q21;q26.2), accounts for approximately 1% of newly diagnosed AML. They involve aberrant relocation of the distal GATA2 hematopoietic enhancer with MYB binding sites, leading to EVI1 overexpression from the MDS1-EVI1 complex (MECOM) locus. EVI1 is a transcriptional regulator that plays a role in proliferation, differentiation and maintenance of the AML stem cell-like phenotype. In MECOM-r AML, due to the GATA2 haplo-insufficiency with overexpression and increased activity of EVI1, AML stem/progenitor cells exhibit aggressive proliferation, are therapy refractory and display poor overall survival. Therefore, there is an unmet need to develop and test novel targeted therapies to improve outcomes in AML with MECOM-r and EVI1 overexpression. BRG1 (SMARCA4) and BRM (SMARCA2) are the core ATPases within the chromatin remodeling BAF complexes that regulate gene transcription. FHD-286 is a potent, selective, first in the class inhibitor of BRG1/BRM in clinical development as an AML therapy. Our present studies demonstrate that exposure to FHD-286 (10 to 100 nM) for 4 to 7 days induced CD11b expression with morphologic features of differentiation leading to loss of viability in AML cell lines and patient-derived (PD) AML cells with MECOM-r. FHD-286 treatment caused whole-genome, concordant, up- or down-regulations in H3K27Ac ChIP-Seq peaks and the RNA-Seq-determined mRNA expressions of specific loci, including significant reduction in the gene-sets of MYC targets and repression of EVI1. Immunoblot analysis showed that FHD-286 treatment reduced EVI1 protein expression. Additionally, mass spectrometry on MECOM-r AML cells treated with FHD-286 showed log2 fold-reductions in EVI1, c-Myc, CD44, c-KIT, CD93, CDK4 and PLK1 protein levels. In mass cytometry-determined, phenotypically defined AML stem/progenitor cells, FHD-286 treatment also reduced EVI1 expression. Co-treatment with FHD-286 and decitabine, BET inhibitor (OTX015), or HAT inhibitor GNE-781 exerted synergistic in vitro lethality against MECOM-r AML cell lines and PD AML cells (Delta synergy scores &amp;gt; 5 by the ZIP method). Finally, as compared to treatment with each drug alone or vehicle control, in PD xenograft (PDX) models of AML cells with MECOM-r, co-treatment with FHD-286 and decitabine or OTX015 significantly reduced AML burden and improved overall survival of the NSG mice, without inducing significant toxicity. Taken together, these findings highlight the promise of FHD-286 treatment alone and in rational combinations in exerting significant anti-AML efficacy against cellular models of AML, especially those with MECOM-r and EVI1 overexpression. Citation Format: Warren C. Fiskus, Christopher P. Mill, Jessica Piel, Murphy Hentemann, Christine E. Birdwell, Kaberi Das, Hanxi Hou, John A. Davis, Surbhi Sharma, Tapan M. Kadia, Naval Daver, Sanam Loghavi, Courtney D. DiNardo, Kapil N. Bhalla. Superior preclinical efficacy of BRG1/BRM inhibitor combined with BET inhibitor or decitabine against MECOM-rearranged AML [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 451.