Superior preclinical efficacy of co-treatment with BRG1/BRM and FLT3 inhibitor against AML cells with FLT3 mutations
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.
Authors
- Christine Birdwell
- Courtney Denton Dinardo (ORCID: https://orcid.org/0000-0001-9003-0390)
- Jessica Piel
- Anna Malovannaya (ORCID: https://orcid.org/0000-0003-2953-6485)
- Christopher P. Mill (ORCID: https://orcid.org/0000-0003-0957-6009)
- Lauren B. Flores (ORCID: https://orcid.org/0009-0009-5611-6014)
- Tapan Mahendra Kadia (ORCID: https://orcid.org/0000-0002-9892-9832)
- Antrix Jain (ORCID: https://orcid.org/0000-0002-2815-3645)
- Koji Sasaki (ORCID: https://orcid.org/0000-0002-9140-0610)
- Patrick K. Reville (ORCID: https://orcid.org/0000-0001-8433-3360)
- Naval Guastad Daver (ORCID: https://orcid.org/0000-0001-7103-373X)
- Koichi Takahashi (ORCID: https://orcid.org/0000-0002-8027-9659)
- Branko Cuglievan (ORCID: https://orcid.org/0000-0002-6917-2244)
- Murphy Hentemann
- Sanam Loghavi (ORCID: https://orcid.org/0000-0001-8980-3202)
- Warren C. Fiskus (ORCID: https://orcid.org/0000-0002-7343-6214)
- Xiaoping Su (ORCID: https://orcid.org/0000-0003-1824-943X)
- Kaberi Das (ORCID: https://orcid.org/0000-0003-4702-0386)
- Hanxi Hou (ORCID: https://orcid.org/0000-0002-1951-3522)
- Kapil N. Bhalla (ORCID: https://orcid.org/0000-0001-5209-5126)
- Danielle Hammond (ORCID: https://orcid.org/0000-0002-6017-2264)
- Mike Collins
- John A. Davis
Institutions
- The University of Texas MD Anderson Cancer Center (US)
- Baylor College of Medicine (US)
- Foghorn Therapeutics (United States) (US)
Publication Details
- Journal
- Blood Cancer Journal
- Published
- 2025-03-15
- DOI
- https://doi.org/10.1038/s41408-025-01251-7
- Citations
- 1
- Primary Topic
- Acute Myeloid Leukemia Research
- Type
- article
- Field-Weighted Citation Impact
- 1.77