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|Ref Type||Journal Article|
|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.|
|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.|
|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|