Reference Detail

Ref Type

Journal Article

PMID

(38437498)

Authors

Fiskus W, Piel J, Collins MP, Hentemann M, Cuglievan B, Mill CP, Birdwell C, Das K, Davis JA, Hou H, Jain A, Malovannaya A, Kadia TM, Daver NG, Sasaki K, Takahashi K, Hammond D, Reville PK, Wang J, Loghavi S, Sen R, Ruan X, Su X, Flores L, DiNardo CD, Bhalla KN

Title

BRG1/BRM inhibitor targets AML stem cells and exerts superior preclinical efficacy combined with BET or Menin inhibitor.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Blood			2024 Feb 16		Blood

URL

Abstract Text

BRG1 (SMARCA4) and BRM (SMARCA2) are the mutually exclusive core ATPases of the chromatin remodeling BAF (BRG1/BRM-associated factor) complexes. They enable transcription factors/co-factors to access enhancers/promoter and modulate gene-expressions responsible for cell growth and differentiation of AML stem/progenitor cells. In AML with MLL1r (MLL1 rearrangement) or mutant (mt) NPM1, although Menin inhibitor (MI) treatment induces clinical remissions, most patients either fail to respond or relapse, some harboring Menin mutations. FHD-286 is an orally bioavailable, selective inhibitor of BRG1/BRM under clinical development in AML. Present studies show that FHD-286 induces differentiation and lethality in AML cells with MLL1r or mtNPM1, concomitantly causing perturbed chromatin accessibility and repression of c-Myc, PU.1 and CDK4/6. Co-treatment with FHD-286 and decitabine, BET inhibitor (BETi) or MI, or venetoclax synergistically induced in vitro lethality in AML cells with MLL1r or mtNPM1. In patient-derived xenograft (PDX) models of AML with MLL1r or mtNPM1, FHD-286 treatment reduced AML burden, improved survival, and attenuated AML-initiating potential of stem-progenitor cells. Compared to each drug, co-treatment with FHD-286 and BETi, MI, decitabine or venetoclax significantly reduced AML burden and improved survival, without inducing significant toxicity. These findings highlight the FHD-286-based combinations as promising therapy of AML with MLL1r or mtNPM1.

Filtering

Case insensitive filtering will display rows if any text in any cell matches the filter term
Use simple literal full or partial string matches
Separate multiple filter terms with a space. Any order may be used (i. e. a b c and c b a are equivalent )
Filtering will only apply to rows that are already loaded on the page. Filtering has no impact on query parameters.
Use quotes to match on a longer phrase with spaces (i.e. "mtor c1483f")

Sorting

Generally, the default sort order for tables is set to be first column ascending; however, specific tables may set a different default sort order.
Click on any column header arrows to sort by that column
Hold down the Shift key and click multiple columns to sort by more than one column. Be sure to set ascending or descending order for a given column before moving on to the next column.

Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
FHD-286	FHD-286	1	2

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
FHD-286		FHD286\|FHD 286		FHD-286 inhibits SMARCA4 (BRG1) and SMARCA2 (BRM), which may lead to altered chromatin accessibility and decreased tumor growth (Cancer Res 2022;82(12_Suppl):Abstract nr ND14, PMID: 38437498).

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	acute myeloid leukemia	sensitive	FHD-286 + Revumenib	Preclinical - Patient cell culture	Actionable	In a preclinical study, the combination of FHD-286 and Revumenib (SNDX-5613) synergistically inhibited viability of acute myeloid leukemia cell lines and a patient-derived cell line harboring a KMT2A rearrangement in culture (PMID: 38437498).	38437498
KMT2A rearrange	acute myeloid leukemia	sensitive	FHD-286 + Venetoclax	Preclinical - Patient cell culture	Actionable	In a preclinical study, the combination of FHD-286 and Venclexta (venetoclax) synergistically inhibited viability of acute myeloid leukemia cell lines and a patient-derived cell line harboring a KMT2A rearrangement in culture (PMID: 38437498).	38437498
KMT2A rearrange	acute myeloid leukemia	sensitive	FHD-286	Preclinical - Patient cell culture	Actionable	In a preclinical study, FHD-286 induced differentiation and decreased viability in acute myeloid leukemia cell lines and patient-derived cells harboring a KMT2A rearrangement in culture (PMID: 38437498).	38437498
KMT2A rearrange	acute myeloid leukemia	sensitive	Birabresib + FHD-286	Preclinical - Patient cell culture	Actionable	In a preclinical study, the combination of FHD-286 and Birabresib (OTX015) synergistically inhibited viability of acute myeloid leukemia cell lines and a patient-derived cell line harboring a KMT2A rearrangement in culture (PMID: 38437498).	38437498
KMT2A rearrange	acute myeloid leukemia	sensitive	Decitabine + FHD-286	Preclinical - Cell culture	Actionable	In a preclinical study, the combination of FHD-286 and Dacogen (decitabine) synergistically inhibited viability of acute myeloid leukemia cell lines harboring a KMT2A rearrangement in culture (PMID: 38437498).	38437498