Superior Preclinical Efficacy of Co-Treatment With BRG1/BRM and FLT3 Inhibitor Against AML Cells With FLT3 Mutations

Authors

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

Publication Date

3-15-2025

Journal

Blood Cancer Journal

DOI

10.1038/s41408-025-01251-7

PMID

40089460

PMCID

PMC11910597

PubMedCentral® Posted Date

3-15-2025

PubMedCentral® Full Text Version

Post-print

Abstract

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.

Keywords

Humans, fms-Like Tyrosine Kinase 3, Leukemia, Myeloid, Acute, Animals, DNA Helicases, Nuclear Proteins, Mice, Mutation, Transcription Factors, Xenograft Model Antitumor Assays, Cell Line, Tumor, Protein Kinase Inhibitors, Antineoplastic Combined Chemotherapy Protocols, Female

Published Open-Access

yes

Recommended Citation

Fiskus, Warren; Mill, Christopher P; Piel, Jessica; et al., "Superior Preclinical Efficacy of Co-Treatment With BRG1/BRM and FLT3 Inhibitor Against AML Cells With FLT3 Mutations" (2025). Faculty, Staff and Student Publications. 5046.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5046