Venetoclax Is Effective in Small-Cell Lung Cancers with High BCL-2 Expression.
Clin Cancer Res
; 24(2): 360-369, 2018 01 15.
Article
en En
| MEDLINE
| ID: mdl-29118061
ABSTRACT
Purpose:
Small-cell lung cancer (SCLC) is an often-fatal neuroendocrine carcinoma usually presenting as extensive disease, carrying a 3% 5-year survival. Despite notable advances in SCLC genomics, new therapies remain elusive, largely due to a lack of druggable targets.ExperimentalDesign:
We used a high-throughput drug screen to identify a venetoclax-sensitive SCLC subpopulation and validated the findings with multiple patient-derived xenografts of SCLC.Results:
Our drug screen consisting of a very large collection of cell lines demonstrated that venetoclax, an FDA-approved BCL-2 inhibitor, was found to be active in a substantial fraction of SCLC cell lines. Venetoclax induced BIM-dependent apoptosis in vitro and blocked tumor growth and induced tumor regressions in mice bearing high BCL-2-expressing SCLC tumors in vivo BCL-2 expression was a predictive biomarker for sensitivity in SCLC cell lines and was highly expressed in a subset of SCLC cell lines and tumors, suggesting that a substantial fraction of patients with SCLC could benefit from venetoclax. Mechanistically, we uncover a novel role for gene methylation that helped discriminate high BCL-2-expressing SCLCs.Conclusions:
Altogether, our findings identify venetoclax as a promising new therapy for high BCL-2-expressing SCLCs. Clin Cancer Res; 24(2); 360-9. ©2017 AACR.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Sulfonamidas
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Expresión Génica
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Compuestos Bicíclicos Heterocíclicos con Puentes
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Proteínas Proto-Oncogénicas c-bcl-2
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Carcinoma Pulmonar de Células Pequeñas
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Neoplasias Pulmonares
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Antineoplásicos
Tipo de estudio:
Prognostic_studies
Límite:
Animals
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Humans
Idioma:
En
Revista:
Clin Cancer Res
Asunto de la revista:
NEOPLASIAS
Año:
2018
Tipo del documento:
Article