Targeting Bfl-1 via acute CDK9 inhibition overcomes intrinsic BH3-mimetic resistance in lymphomas.
Blood
; 137(21): 2947-2957, 2021 05 27.
Article
en En
| MEDLINE
| ID: mdl-33259592
BH3 mimetics like venetoclax target prosurvival Bcl-2 family proteins and are important therapeutics in the treatment of hematological malignancies. We demonstrate that endogenous Bfl-1 expression can render preclinical lymphoma tumor models insensitive to Mcl-1 and Bcl-2 inhibitors. However, suppression of Bfl-1 alone was insufficient to fully induce apoptosis in Bfl-1-expressing lymphomas, highlighting the need for targeting additional prosurvival proteins in this context. Importantly, we demonstrated that cyclin-dependent kinase 9 (CDK9) inhibitors rapidly downregulate both Bfl-1 and Mcl-1, inducing apoptosis in BH3-mimetic-resistant lymphoma cell lines in vitro and driving in vivo tumor regressions in diffuse large B-cell lymphoma patient-derived xenograft models expressing Bfl-1. These data underscore the need to clinically develop CDK9 inhibitors, like AZD4573, for the treatment of lymphomas using Bfl-1 as a selection biomarker.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Sulfonamidas
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Linfoma de Células B Grandes Difuso
/
Resistencia a Antineoplásicos
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Compuestos Bicíclicos Heterocíclicos con Puentes
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Proteínas Proto-Oncogénicas c-bcl-2
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Quinasa 9 Dependiente de la Ciclina
/
Compuestos Macrocíclicos
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Terapia Molecular Dirigida
/
Proteínas de Neoplasias
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Female
/
Humans
Idioma:
En
Revista:
Blood
Año:
2021
Tipo del documento:
Article
Pais de publicación:
Estados Unidos