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Ref Type Journal Article
PMID (30664779)
Authors Sharifnia T, Wawer MJ, Chen T, Huang QY, 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
Title Small-molecule targeting of brachyury transcription factor addiction in chordoma.
Journal Nature medicine
Date 2019 Jan 21
Abstract Text 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.


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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown chordoma not applicable Alvocidib Preclinical - Cell culture Actionable In a preclinical study, Alvocidib (flavopiridol) treatment reduced viability of chordoma cells in culture (PMID: 30664779). 30664779
Unknown unknown chordoma not applicable Dinaciclib Preclinical - Cell culture Actionable In a preclinical study, Dinaciclib (SCH 727965) treatment reduced viability of chordoma cells in culture (PMID: 30664779). 30664779
Unknown unknown chordoma not applicable THZ1 Preclinical - Cell line xenograft Actionable In a preclinical study, THZ1 treatment inhibited phosphorylation of Polr2a, reduced viability, and induced apoptosis in chordoma cells in culture, and inhibited tumor growth in a cell line xenograft model (PMID: 30664779). 30664779