|
| Status |
Public on Jan 20, 2019 |
| Title |
Small-molecule targeting of brachyury transcription factor addiction in chordoma [ATAC-Seq] |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
Chordoma is a primary bone cancer with no approved therapy. The identification of therapeutic targets in this disease has been challenging due to the infrequent occurrence of clinically actionable somatic mutations in chordoma tumors. Here we describe the discovery of therapeutically targetable chordoma dependencies via genome-scale CRISPR-Cas9 screening and focused small-molecule sensitivity profiling. These systematic approaches reveal that the developmental transcription factor T (brachyury; TBXT) is the top selectively essential gene in chordoma, and that transcriptional cyclin-dependent kinase (CDK) inhibitors targeting CDK7/12/13 and CDK9 potently suppress chordoma cell proliferation. In other cancer types, transcriptional CDK inhibitors have been observed to downregulate highly expressed, enhancer-associated oncogenic transcription factors (TFs). In chordoma, we find that T is associated with a 1.5-Mb region containing “super-enhancers” and is the most highly expressed super-enhancer-associated TF. Strikingly, transcriptional CDK inhibition leads to preferential and concentration-dependent downregulation of cellular brachyury protein levels in all models tested. Together, these data demonstrate small-molecule targeting of brachyury TF addiction in chordoma, identify a mechanism of T gene regulation that underlies this therapeutic strategy and provide a blueprint for applying systematic genetic and chemical screening approaches to discover vulnerabilities in genomically quiet cancers.
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| |
|
| Overall design |
Paired-end ATAC-Seq profiling in the U-CH2 and MUG-Chor1 chordoma cell lines
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| |
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| Contributor(s) |
Schreiber S, Sharifnia T, Lin C, Kotz J |
| Citation(s) |
30664779 |
| |
| Submission date |
Jan 29, 2018 |
| Last update date |
Jul 26, 2019 |
| Contact name |
James Bradner |
| E-mail(s) |
bradner_computation@dfci.harvard.edu
|
| Organization name |
Dana-Farber Cancer Institute
|
| Department |
Medical Oncology
|
| Lab |
Bradner Lab
|
| Street address |
450 Brookline
|
| City |
Boston |
| State/province |
MA |
| ZIP/Postal code |
02215 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL11154 |
Illumina HiSeq 2000 (Homo sapiens) |
|
| Samples (3) |
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| This SubSeries is part of SuperSeries: |
| GSE109794 |
Small-molecule targeting of brachyury transcription factor addiction in chordoma |
|
| Relations |
| BioProject |
PRJNA432041 |
| SRA |
SRP131674 |
