1. Academic Validation
  2. Superior preclinical efficacy of co-treatment with BRG1/BRM and FLT3 inhibitor against AML cells with FLT3 mutations

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

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. kbhalla@mdanderson.org.
  • # Contributed equally.
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.

Figures
Products