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Ref Type Journal Article
PMID (40089460)
Authors Fiskus W, Mill CP, Piel J, Collins M, Hentemann M, Cuglievan B, Birdwell CE, Das K, Hou H, Davis JA, Jain A, Malovannaya A, Kadia TM, Daver N, Sasaki K, Takahashi K, Hammond D, Reville PK, Flores LB, Loghavi S, Su X, DiNardo CD, Bhalla KN
Title Superior preclinical efficacy of co-treatment with BRG1/BRM and FLT3 inhibitor against AML cells with FLT3 mutations.
Journal Vol Issue Date Pages Journal Short Title
Blood cancer journal 15 1 2025 Mar 15 40 Blood Cancer J
URL
Abstract Text 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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
KMT2A rearrange FLT3 exon 14 ins FLT3 D835Y acute myeloid leukemia sensitive FHD-286 + Quizartinib Preclinical - Cell line xenograft Actionable In a preclinical study, FHD-286 and Vanflyta (quizartinib) synergistically inhibited viability in acute myeloid leukemia cells harboring a KMT2A rearrangement, FLT3-ITD, and FLT3 D835Y in culture, and resulted in increased survival compared to treatment with Vanflyta (quizartinib) alone in a cell line xenograft model (PMID: 40089460). 40089460
KMT2A rearrange FLT3 exon 14 ins FLT3 D835Y acute myeloid leukemia sensitive FHD-286 + Gilteritinib Preclinical - Cell line xenograft Actionable In a preclinical study, FHD-286 and Xospata (gilteritinib) synergistically inhibited viability in acute myeloid leukemia cells harboring a KMT2A rearrangement, FLT3-ITD and FLT3 D835Y in culture, and resulted in greater reduction of tumor burden and increased survival compared to either agent alone in a cell line xenograft model (PMID: 40089460). 40089460
KMT2A rearrange FLT3 exon 14 ins acute myeloid leukemia sensitive FHD-286 + Quizartinib Preclinical - Cell culture Actionable In a preclinical study, FHD-286 and Vanflyta (quizartinib) synergistically inhibited viability in acute myeloid leukemia cells harboring KMT2A rearrangements and FLT3-ITD in culture (PMID: 40089460). 40089460
KMT2A rearrange FLT3 exon 14 ins acute myeloid leukemia sensitive FHD-286 + Gilteritinib Preclinical - Cell culture Actionable In a preclinical study, FHD-286 and Xospata (gilteritinib) synergistically inhibited viability in acute myeloid leukemia cells harboring a KMT2A rearrangement and FLT3-ITD in culture (PMID: 40089460). 40089460