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Status |
Public on Jun 19, 2020 |
Title |
Combined targeting of the BRD4-NUT-p300 axis in NUT midline carcinoma by dual selective bromodomain inhibitor, NEO2734 |
Organism |
Homo sapiens |
Experiment type |
Expression profiling by high throughput sequencing
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Summary |
NUT midline carcinoma (NMC) is a rare, aggressive subtype of squamous carcinoma that is driven by the BRD4-NUT fusion oncoprotein. BRD4, a BET protein, binds to chromatin through its two bromodomains, and NUT recruits the p300 histone acetyltransferse (HAT) to activate transcription of oncogenic target genes. BET selective bromodomain inhibitors have demonstrated on-target activity in NMC patients, but with limited efficacy. P300, like BRD4, contains a bromodomain. We show that combining selective p300/CBP and BET bromodomain inhibitors, GNE-781 and OTX015, respectively, induces synergistic inhibition of NMC growth. Treatment of NMC cells with the novel dual p300/CBP and BET bromodomain selective inhibitor, NEO2734, potently inhibits growth and induces differentiation of NMC cells in vitro; findings that correspond with potentiated transcriptional effects from combined BET and p300 bromodomain inhibition. In three disseminated NMC xenograft models, NEO2734 provided greater growth inhibition, with tumor regression and significant survival benefit seen in two of three models, compared with a lead clinical BET inhibitor or 'standard' chemotherapy.
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Overall design |
High throughput analysis of ribosomal RNA depleted total RNA
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Contributor(s) |
Morrison-Smith C, French CA |
Citation(s) |
32371576, 37645799 |
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Submission date |
Dec 21, 2019 |
Last update date |
Sep 14, 2023 |
Contact name |
Chevaun Morrison-Smith |
E-mail(s) |
cmorrison-smith@bwh.harvard.edu
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Phone |
6175254430
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Organization name |
Brigham and Women's Hospital
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Department |
Pathology
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Lab |
Christopher French
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Street address |
77 AVENUE LOUIS PASTEUR, NRB 652
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City |
BOSTON |
State/province |
MA |
ZIP/Postal code |
02115-5727 |
Country |
USA |
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Platforms (1) |
GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
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Samples (20)
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Relations |
BioProject |
PRJNA597130 |
SRA |
SRP238472 |
Supplementary file |
Size |
Download |
File type/resource |
GSE142481_PER403_797_CPM.txt.gz |
1.7 Mb |
(ftp)(http) |
TXT |
GSE142481_PER403_797_raw_counts.txt.gz |
1.1 Mb |
(ftp)(http) |
TXT |
GSE142481_RAW.tar |
1.3 Gb |
(http)(custom) |
TAR (of TDF) |
SRA Run Selector |
Raw data are available in SRA |
Processed data provided as supplementary file |
Processed data are available on Series record |
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