TY - JOUR
T1 - BRG1/BRM inhibitor targets AML stem cells and exerts superior preclinical efficacy combined with BET or menin inhibitor
AU - Fiskus, Warren
AU - Piel, Jessica
AU - Collins, Mike
AU - Hentemann, Murphy
AU - Cuglievan, Branko
AU - Mill, Christopher P.
AU - Birdwell, Christine E.
AU - Das, Kaberi
AU - Davis, John A.
AU - Hou, Hanxi
AU - Jain, Antrix
AU - Malovannaya, Anna
AU - Kadia, Tapan M.
AU - Daver, Naval
AU - Sasaki, Koji
AU - Takahashi, Koichi
AU - Hammond, Danielle
AU - Reville, Patrick K.
AU - Wang, Jian
AU - Loghavi, Sanam
AU - Sen, Rwik
AU - Ruan, Xinjia
AU - Su, Xiaoping
AU - Flores, Lauren B.
AU - DiNardo, Courtney D.
AU - Bhalla, Kapil N.
N1 - Publisher Copyright:
© 2024 American Society of Hematology
PY - 2024/5/16
Y1 - 2024/5/16
N2 - 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/cofactors to access enhancers/promoter and modulate gene expressions responsible for cell growth and differentiation of acute myeloid leukemia (AML) stem/progenitor cells. In AML with MLL1 rearrangement (MLL1r) or mutant NPM1 (mtNPM1), 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. Cotreatment 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 models of xenografts derived from patients with AML with MLL1r or mtNPM1, FHD-286 treatment reduced AML burden, improved survival, and attenuated AML-initiating potential of stem-progenitor cells. Compared with each drug, cotreatment 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 a promising therapy for AML with MLL1r or mtNPM1.
AB - 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/cofactors to access enhancers/promoter and modulate gene expressions responsible for cell growth and differentiation of acute myeloid leukemia (AML) stem/progenitor cells. In AML with MLL1 rearrangement (MLL1r) or mutant NPM1 (mtNPM1), 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. Cotreatment 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 models of xenografts derived from patients with AML with MLL1r or mtNPM1, FHD-286 treatment reduced AML burden, improved survival, and attenuated AML-initiating potential of stem-progenitor cells. Compared with each drug, cotreatment 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 a promising therapy for AML with MLL1r or mtNPM1.
UR - http://www.scopus.com/inward/record.url?scp=85187188884&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85187188884&partnerID=8YFLogxK
U2 - 10.1182/blood.2023022832
DO - 10.1182/blood.2023022832
M3 - Article
C2 - 38437498
AN - SCOPUS:85187188884
SN - 0006-4971
VL - 143
SP - 2059
EP - 2072
JO - Blood
JF - Blood
IS - 20
ER -