BRG1/Brm Inhibitor Targets Aml Stem Cells and Exerts Superior Preclinical Efficacy Combined With Bet or Menin Inhibitor

Authors

Warren Fiskus
Jessica Piel
Mike Collins
Murphy Hentemann
Branko Cuglievan
Christopher P Mill
Christine E Birdwell
Kaberi Das
John A Davis
Hanxi Hou
Antrix Jain
Anna Malovannaya
Tapan M Kadia
Naval Daver
Koji Sasaki
Koichi Takahashi
Danielle Hammond
Patrick K Reville
Jian Wang
Sanam Loghavi
Rwik Sen
Xinjia Ruan
Xiaoping Su
Lauren B Flores
Courtney D DiNardo
Kapil N Bhalla

Publication Date

5-16-2024

Journal

Blood

Abstract

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.

Keywords

Animals, Humans, Mice, Bromodomain Containing Proteins, Cell Line, Tumor, DNA Helicases, Leukemia, Myeloid, Acute, Neoplastic Stem Cells, Nuclear Proteins, Nucleophosmin, Proto-Oncogene Proteins, Transcription Factors, Xenograft Model Antitumor Assays

DOI

10.1182/blood.2023022832

PMID

38437498

PMCID

PMC11830987

PubMedCentral® Posted Date

2-18-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes