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  • Small-molecule targeting of brachyury transcription factor addiction in chordoma.

Small-molecule targeting of brachyury transcription factor addiction in chordoma.

Nature medicine (2019-01-22)
Tanaz Sharifnia, Mathias J Wawer, Ting Chen, Qing-Yuan Huang, Barbara A Weir, Ann Sizemore, Matthew A Lawlor, Amy Goodale, Glenn S Cowley, Francisca Vazquez, Christopher J Ott, Joshua M Francis, Slim Sassi, Patricia Cogswell, Hadley E Sheppard, Tinghu Zhang, Nathanael S Gray, Paul A Clarke, Julian Blagg, Paul Workman, Josh Sommer, Francis Hornicek, David E Root, William C Hahn, James E Bradner, Kwok K Wong, Paul A Clemons, Charles Y Lin, Joanne D Kotz, Stuart L Schreiber
ABSTRACT

Chordoma is a primary bone cancer with no approved therapy1. The identification of therapeutic targets in this disease has been challenging due to the infrequent occurrence of clinically actionable somatic mutations in chordoma tumors2,3. 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 factors4,5. 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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-RNA polymerase II subunit B1 (phospho-CTD Ser-7) Antibody, clone 4E12, culture supernatant, clone 4E12, from rat
Sigma-Aldrich
Anti-RNA polymerase II subunit B1 (phospho-CTD Ser-5) Antibody, clone 3E8, culture supernatant, clone 3E8, from rat
Sigma-Aldrich
Anti-RNA polymerase II subunit B1 (phospho CTD Ser-2), clone 3E10 (rat monoclonal)., culture supernatant, clone 3E10, from rat