An acetyl-histone vulnerability in PI3K/AKT inhibition-resistant cancers is targetable by both BET and HDAC inhibitors.
Cell Rep
; 34(7): 108744, 2021 02 16.
Article
em En
| MEDLINE
| ID: mdl-33596421
ABSTRACT
Acquisition of resistance to phosphatidylinositol 3-kinase (PI3K)/AKT-targeted monotherapy implies the existence of common resistance mechanisms independent of cancer type. Here, we demonstrate that PI3K/AKT inhibitors cause glycolytic crisis, acetyl-coenzyme A (CoA) shortage, and a global decrease in histone acetylation. In addition, PI3K/AKT inhibitors induce drug resistance by selectively augmenting histone H3 lysine 27 acetylation (H3K27ac) and binding of CBP/p300 and BRD4 proteins at a subset of growth factor and receptor (GF/R) gene loci. BRD4 occupation at these loci and drug-resistant cell growth are vulnerable to both bromodomain and histone deacetylase (HDAC) inhibitors. Little or no occupation of HDAC proteins at the GF/R gene loci underscores the paradox that cells respond equivalently to the two classes of inhibitors with opposite modes of action. Targeting this unique acetyl-histone-related vulnerability offers two clinically viable strategies to overcome PI3K/AKT inhibitor resistance in different cancers.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Histonas
/
Receptores de Superfície Celular
/
Fosfatidilinositol 3-Quinases
/
Proteínas Proto-Oncogênicas c-akt
/
Inibidores de Histona Desacetilases
/
Inibidores de Fosfoinositídeo-3 Quinase
/
Neoplasias
/
Proteínas do Tecido Nervoso
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
/
Male
Idioma:
En
Revista:
Cell Rep
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
China