Transcriptional Dependencies in Diffuse Intrinsic Pontine Glioma.
Cancer Cell
; 31(5): 635-652.e6, 2017 05 08.
Article
en En
| MEDLINE
| ID: mdl-28434841
ABSTRACT
Diffuse intrinsic pontine glioma (DIPG) is a fatal pediatric cancer with limited therapeutic options. The majority of cases of DIPG exhibit a mutation in histone-3 (H3K27M) that results in oncogenic transcriptional aberrancies. We show here that DIPG is vulnerable to transcriptional disruption using bromodomain inhibition or CDK7 blockade. Targeting oncogenic transcription through either of these methods synergizes with HDAC inhibition, and DIPG cells resistant to HDAC inhibitor therapy retain sensitivity to CDK7 blockade. Identification of super-enhancers in DIPG provides insights toward the cell of origin, highlighting oligodendroglial lineage genes, and reveals unexpected mechanisms mediating tumor viability and invasion, including potassium channel function and EPH receptor signaling. The findings presented demonstrate transcriptional vulnerabilities and elucidate previously unknown mechanisms of DIPG pathobiology.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Fenilendiaminas
/
Pirimidinas
/
Azepinas
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Transcripción Genética
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Triazoles
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Protocolos de Quimioterapia Combinada Antineoplásica
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Regulación Neoplásica de la Expresión Génica
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Neoplasias del Tronco Encefálico
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Inhibidores de Proteínas Quinasas
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Inhibidores de Histona Desacetilasas
Tipo de estudio:
Prognostic_studies
Idioma:
En
Año:
2017
Tipo del documento:
Article