Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA185813 | ENA |
REPOSITORIES: ENA
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Project description:Bromodomain inhibition comprises a promising therapeutic strategy in cancer, particularly for hematologic malignancies. To date, however, genomic biomarkers to direct clinical translation have been lacking. We conducted a cell-based screen of genetically-defined cancer cell lines using a prototypical inhibitor of BET bromodomains. Integration of genetic features with chemosensitivity data revealed a robust correlation between MYCN amplification and sensitivity to bromodomain inhibition. We characterized the mechanistic and translational significance of this finding in neuroblastoma, a childhood cancer with frequent amplification of MYCN. Genome-wide expression analysis demonstrated downregulation of the MYCN transcriptional program accompanied by suppression of MYCN transcription. Functionally, bromodomain-mediated inhibition of MYCN impaired growth and induced apoptosis in neuroblastoma. BRD4 knock-down phenocopied these effects, establishing BET bromodomains as transcriptional regulators of MYCN. BET inhibition conferred a significant survival advantage in three in vivo neuroblastoma models, providing a compelling rationale for developing BET bromodomain inhibitors in patients with neuroblastoma. Significance: Biomarkers of response to small-molecule inhibitors of BET bromodomains, a new compound class with promising anti-cancer activity, have been lacking. Here, we reveal MYCN amplification as a strong genetic predictor of sensitivity to BET bromodomain inhibitors, demonstrate a mechanistic rationale for this finding, and provide a translational framework for clinical trial development of BET bromodomain inhibitors for pediatric patients with MYCN-amplified neuroblastoma. JQ1 is a novel thieno-triazolo-1,4-diazepine, which displaces BET bromodomains from chromatin by competitively binding to the acetyl lysine recognition pocket. BE(2)-C and Kelly cells were treated in triplicate with 1 µM JQ1 or DMSO for 24 hours. RNA was extracted and a decrease in MYCN transcript was confirmed by real time RT-PCR as described above. The samples were profiled using the Affymetrix PrimeView Human Gene Expression Array (Affymetrix) at Beth Israel Deaconess Medical Center (Boston, MA, USA).
2013-02-25 | E-GEOD-43392 | biostudies-arrayexpress
Project description:Bromodomain inhibition comprises a promising therapeutic strategy in cancer, particularly for hematologic malignancies. To date, however, genomic biomarkers to direct clinical translation have been lacking. We conducted a cell-based screen of genetically-defined cancer cell lines using a prototypical inhibitor of BET bromodomains. Integration of genetic features with chemosensitivity data revealed a robust correlation between MYCN amplification and sensitivity to bromodomain inhibition. We characterized the mechanistic and translational significance of this finding in neuroblastoma, a childhood cancer with frequent amplification of MYCN. Genome-wide expression analysis demonstrated downregulation of the MYCN transcriptional program accompanied by suppression of MYCN transcription. Functionally, bromodomain-mediated inhibition of MYCN impaired growth and induced apoptosis in neuroblastoma. BRD4 knock-down phenocopied these effects, establishing BET bromodomains as transcriptional regulators of MYCN. BET inhibition conferred a significant survival advantage in three in vivo neuroblastoma models, providing a compelling rationale for developing BET bromodomain inhibitors in patients with neuroblastoma. Significance: Biomarkers of response to small-molecule inhibitors of BET bromodomains, a new compound class with promising anti-cancer activity, have been lacking. Here, we reveal MYCN amplification as a strong genetic predictor of sensitivity to BET bromodomain inhibitors, demonstrate a mechanistic rationale for this finding, and provide a translational framework for clinical trial development of BET bromodomain inhibitors for pediatric patients with MYCN-amplified neuroblastoma.
2013-02-25 | GSE43392 | GEO
Project description:Epigenetic targeting of immunocheckpoint PD-L1 by BET bromodomain inhibition
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Project description:Bromodomain-containing protein 4 (BRD4) functions as an epigenetic reader and binds to so-called super-enhancer regions of driving oncogenes such as MYC in cancer. We investigated the possibility to target super-enhancer regulated genes in neuroblastoma and in MYCN amplified disease in particular. We used OTX015, the first small-molecule BRD4 inhibitor to enter clinical phase I/II trials in adults, to test the feasibility to specifically target super-enhancer regulated gene-expression in neuroblastoma. BRD4 inhibition lead to significant transcriptional down-regulation of genes that were associated with super-enhancers, supporting the notion that BRD4 preferentially acts at these chromatin sites. BRD4 inhibition not only attenuated MYCN transcription but most significantly affected MYCN-regulated transcriptional programs.
2016-07-03 | E-MTAB-3672 | biostudies-arrayexpress
Project description:Targeting EZH2 in MYCN-amplified Neuroblastoma [RNA-seq]
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Project description:Targeting EZH2 in MYCN-amplified Neuroblastoma [ChIP-seq]
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Project description:Dual targeting of MYC and CYCLON by BET bromodomain inhibition optimizes Rituximab response in lymphoma.
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Project description:Gene expression study in Neuroblastoma after BET inhibition
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