Effective Menin inhibitor-based combinations against AML with MLL rearrangement or NPM1 mutation (NPM1c).
Blood Cancer J
; 12(1): 5, 2022 01 11.
Article
em En
| MEDLINE
| ID: mdl-35017466
ABSTRACT
Treatment with Menin inhibitor (MI) disrupts the interaction between Menin and MLL1 or MLL1-fusion protein (FP), inhibits HOXA9/MEIS1, induces differentiation and loss of survival of AML harboring MLL1 re-arrangement (r) and FP, or expressing mutant (mt)-NPM1. Following MI treatment, although clinical responses are common, the majority of patients with AML with MLL1-r or mt-NPM1 succumb to their disease. Pre-clinical studies presented here demonstrate that genetic knockout or degradation of Menin or treatment with the MI SNDX-50469 reduces MLL1/MLL1-FP targets, associated with MI-induced differentiation and loss of viability. MI treatment also attenuates BCL2 and CDK6 levels. Co-treatment with SNDX-50469 and BCL2 inhibitor (venetoclax), or CDK6 inhibitor (abemaciclib) induces synergistic lethality in cell lines and patient-derived AML cells harboring MLL1-r or mtNPM1. Combined therapy with SNDX-5613 and venetoclax exerts superior in vivo efficacy in a cell line or PD AML cell xenografts harboring MLL1-r or mt-NPM1. Synergy with the MI-based combinations is preserved against MLL1-r AML cells expressing FLT3 mutation, also CRISPR-edited to introduce mtTP53. These findings highlight the promise of clinically testing these MI-based combinations against AML harboring MLL1-r or mtNPM1.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Leucemia Mieloide Aguda
/
Histona-Lisina N-Metiltransferase
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Proteínas Proto-Oncogênicas
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Proteína de Leucina Linfoide-Mieloide
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Nucleofosmina
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Antineoplásicos
Limite:
Humans
Idioma:
En
Revista:
Blood Cancer J
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Estados Unidos