Superior preclinical efficacy of co-treatment with BRG1/BRM and FLT3 inhibitor against AML cells with FLT3 mutations

  • Blood Cancer J. 2025 Mar 15;15(1):40. doi: 10.1038/s41408-025-01251-7.
Warren Fiskus  #  1 ,  Christopher P Mill  #  1 ,  Jessica Piel  2 ,  Mike Collins  2 ,  Murphy Hentemann  2 ,  Branko Cuglievan  1 ,  Christine E Birdwell  1 ,  Kaberi Das  1 ,  Hanxi Hou  1 ,  John A Davis  1 ,  Antrix Jain  3 ,  Anna Malovannaya  3 ,  Tapan M Kadia  1 ,  Naval Daver  1 ,  Koji Sasaki  1 ,  Koichi Takahashi  1 ,  Danielle Hammond  1 ,  Patrick K Reville  1 ,  Lauren B Flores  1 ,  Sanam Loghavi  1 ,  Xiaoping Su  1 ,  Courtney D DiNardo  1 ,  Kapil N Bhalla  4
Affiliations
  • 1. The University of Texas M.D. Anderson Cancer Center, Houston, TX, 77030, USA.
  • 2. Foghorn Therapeutics, Cambridge, MA, 02139, USA.
  • 3. Baylor College of Medicine, Houston, TX, 77030, USA.
  • 4. The University of Texas M.D. Anderson Cancer Center, Houston, TX, 77030, USA. [email protected].
  • # Contributed equally.
PMID: 40089460 DOI: 10.1038/s41408-025-01251-7
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.

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