Small-molecule targeting of brachyury transcription factor addiction in chordoma.
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ICR Authors
Authors
Sharifnia, T
Wawer, MJ
Chen, T
Huang, Q-Y
Weir, BA
Sizemore, A
Lawlor, MA
Goodale, A
Cowley, GS
Vazquez, F
Ott, CJ
Francis, JM
Sassi, S
Cogswell, P
Sheppard, HE
Zhang, T
Gray, NS
Clarke, PA
Blagg, J
Workman, P
Sommer, J
Hornicek, F
Root, DE
Hahn, WC
Bradner, JE
Wong, KK
Clemons, PA
Lin, CY
Kotz, JD
Schreiber, SL
Wawer, MJ
Chen, T
Huang, Q-Y
Weir, BA
Sizemore, A
Lawlor, MA
Goodale, A
Cowley, GS
Vazquez, F
Ott, CJ
Francis, JM
Sassi, S
Cogswell, P
Sheppard, HE
Zhang, T
Gray, NS
Clarke, PA
Blagg, J
Workman, P
Sommer, J
Hornicek, F
Root, DE
Hahn, WC
Bradner, JE
Wong, KK
Clemons, PA
Lin, CY
Kotz, JD
Schreiber, SL
Document Type
Journal Article
Date
2019-02
Date Accepted
2018-11-26
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.
Citation
Nature medicine, 2019, 25 (2), pp. 292 - 300
Source Title
Publisher
ISSN
1078-8956
eISSN
1546-170X
Collections
Research Team
Signal Transduction & Molecular Pharmacology