dc.contributor.author | Sharifnia, T | |
dc.contributor.author | Wawer, MJ | |
dc.contributor.author | Chen, T | |
dc.contributor.author | Huang, Q-Y | |
dc.contributor.author | Weir, BA | |
dc.contributor.author | Sizemore, A | |
dc.contributor.author | Lawlor, MA | |
dc.contributor.author | Goodale, A | |
dc.contributor.author | Cowley, GS | |
dc.contributor.author | Vazquez, F | |
dc.contributor.author | Ott, CJ | |
dc.contributor.author | Francis, JM | |
dc.contributor.author | Sassi, S | |
dc.contributor.author | Cogswell, P | |
dc.contributor.author | Sheppard, HE | |
dc.contributor.author | Zhang, T | |
dc.contributor.author | Gray, NS | |
dc.contributor.author | Clarke, PA | |
dc.contributor.author | Blagg, J | |
dc.contributor.author | Workman, P | |
dc.contributor.author | Sommer, J | |
dc.contributor.author | Hornicek, F | |
dc.contributor.author | Root, DE | |
dc.contributor.author | Hahn, WC | |
dc.contributor.author | Bradner, JE | |
dc.contributor.author | Wong, KK | |
dc.contributor.author | Clemons, PA | |
dc.contributor.author | Lin, CY | |
dc.contributor.author | Kotz, JD | |
dc.contributor.author | Schreiber, SL | |
dc.date.accessioned | 2020-03-06T12:22:42Z | |
dc.date.issued | 2019-02 | |
dc.identifier.citation | Nature medicine, 2019, 25 (2), pp. 292 - 300 | |
dc.identifier.issn | 1078-8956 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/3536 | |
dc.identifier.eissn | 1546-170X | |
dc.identifier.doi | 10.1038/s41591-018-0312-3 | |
dc.description.abstract | Chordoma is a primary bone cancer with no approved therapy 1 . The identification of therapeutic targets in this disease has been challenging due to the infrequent occurrence of clinically actionable somatic mutations in chordoma tumors 2,3 . 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 4,5 . 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 transcription factor. Notably, transcriptional CDK inhibition leads to preferential and concentration-dependent downregulation of cellular brachyury protein levels in all models tested. In vivo, CDK7/12/13-inhibitor treatment substantially reduces tumor growth. Together, these data demonstrate small-molecule targeting of brachyury transcription factor 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. | |
dc.format | Print-Electronic | |
dc.format.extent | 292 - 300 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.rights.uri | https://www.rioxx.net/licenses/all-rights-reserved | |
dc.subject | Humans | |
dc.subject | Chordoma | |
dc.subject | Cyclin-Dependent Kinases | |
dc.subject | T-Box Domain Proteins | |
dc.subject | Fetal Proteins | |
dc.subject | Transcription Factors | |
dc.subject | Protein Kinase Inhibitors | |
dc.subject | Cell Proliferation | |
dc.subject | Down-Regulation | |
dc.subject | Genes, Essential | |
dc.subject | Small Molecule Libraries | |
dc.title | Small-molecule targeting of brachyury transcription factor addiction in chordoma. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2018-11-26 | |
rioxxterms.versionofrecord | 10.1038/s41591-018-0312-3 | |
rioxxterms.licenseref.uri | https://www.rioxx.net/licenses/all-rights-reserved | |
rioxxterms.licenseref.startdate | 2019-02 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Nature medicine | |
pubs.issue | 2 | |
pubs.notes | No embargo | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Signal Transduction & Molecular Pharmacology | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Signal Transduction & Molecular Pharmacology | |
pubs.publication-status | Published | |
pubs.volume | 25 | |
pubs.embargo.terms | No embargo | |
icr.researchteam | Signal Transduction & Molecular Pharmacology | en_US |
dc.contributor.icrauthor | Clarke, Paul | |