CDK7 inhibition suppresses super-enhancer-linked oncogenic transcription in MYCN-driven cancer.
Cell
; 159(5): 1126-1139, 2014 Nov 20.
Article
em En
| MEDLINE
| ID: mdl-25416950
ABSTRACT
The MYC oncoproteins are thought to stimulate tumor cell growth and proliferation through amplification of gene transcription, a mechanism that has thwarted most efforts to inhibit MYC function as potential cancer therapy. Using a covalent inhibitor of cyclin-dependent kinase 7 (CDK7) to disrupt the transcription of amplified MYCN in neuroblastoma cells, we demonstrate downregulation of the oncoprotein with consequent massive suppression of MYCN-driven global transcriptional amplification. This response translated to significant tumor regression in a mouse model of high-risk neuroblastoma, without the introduction of systemic toxicity. The striking treatment selectivity of MYCN-overexpressing cells correlated with preferential downregulation of super-enhancer-associated genes, including MYCN and other known oncogenic drivers in neuroblastoma. These results indicate that CDK7 inhibition, by selectively targeting the mechanisms that promote global transcriptional amplification in tumor cells, may be useful therapy for cancers that are driven by MYC family oncoproteins.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Fenilenodiaminas
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Pirimidinas
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Proteínas Nucleares
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Proteínas Oncogênicas
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Quinases Ciclina-Dependentes
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Inibidores de Proteínas Quinases
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Modelos Animais de Doenças
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Neuroblastoma
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article