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Small-molecule targeting of brachyury transcription factor addiction in chordoma

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

Nature medicine, 2019-02, Vol.25 (2), p.292-300 [Periódico revisado por pares]

United States: Nature Publishing Group

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Small-molecule targeting of brachyury transcription factor addiction in chordoma
Autor: Sharifnia, Tanaz ; Wawer, Mathias J ; Chen, Ting ; Huang, Qing-Yuan ; Weir, Barbara A ; Sizemore, Ann ; Lawlor, Matthew A ; Goodale, Amy ; Cowley, Glenn S ; Vazquez, Francisca ; Ott, Christopher J ; Francis, Joshua M ; Sassi, Slim ; Cogswell, Patricia ; Sheppard, Hadley E ; Zhang, Tinghu ; Gray, Nathanael S ; Clarke, Paul A ; Blagg, Julian ; Workman, Paul ; Sommer, Josh ; Hornicek, Francis ; Root, David E ; Hahn, William C ; Bradner, James E ; Wong, Kwok K ; Clemons, Paul A ; Lin, Charles Y ; Kotz, Joanne D ; Schreiber, Stuart L
Assuntos: Addictions ; Bone cancer ; Brachyura ; Brachyury protein ; Cancer ; Cancer screening ; Care and treatment ; Cell proliferation ; Cell Proliferation - drug effects ; Chordoma - genetics ; Chordoma - metabolism ; Chordoma - pathology ; Criminal investigation ; CRISPR ; Cyclin-dependent kinase ; Cyclin-dependent kinases ; Cyclin-Dependent Kinases - metabolism ; Diagnosis ; Down-Regulation - drug effects ; Embryonal tumors ; Enhancers ; Fetal Proteins - metabolism ; Gene expression ; Gene mutation ; Gene mutations ; Gene regulation ; Genes ; Genes, Essential ; Genetic aspects ; Genetic regulation ; Genetic transcription ; Genomes ; Genomics ; Humans ; Inhibitors ; Kinases ; Medical schools ; Mutation ; Organic chemistry ; Protein Kinase Inhibitors - pharmacology ; Proteins ; Risk factors ; Screening ; Small Molecule Libraries - pharmacology ; T-Box Domain Proteins - metabolism ; Target recognition ; Therapeutic applications ; Transcription (Genetics) ; Transcription factors ; Transcription Factors - metabolism ; Tumors ; Tumors, Embryonal
É parte de: Nature medicine, 2019-02, Vol.25 (2), p.292-300
Notas: T.S., C.Y.L, J.D.K., and S.L.S. designed and supervised the study. T.S., T.C., Q.-Y.H., M.A.L., A.G., and C.J.O. performed experiments: T.S. performed small-molecule sensitivity screening, low-throughput genetic-perturbation and small-molecule sensitivity experiments, RNA sequencing experiments, RT-qPCR, and immunoblotting; T.C. and Q.-Y.H. performed in vivo experiments; M.A.L. performed ChIP-sequencing experiments with assistance from T.S.; A.G. performed genome-scale CRISPR-Cas9 screening with assistance from T.S.; and C.J.O performed ATAC-sequencing experiments. M.J.W. performed analysis of RT-qPCR, RNA-sequencing and whole-exome sequencing data. B.A.W. and A.S. performed analysis of genome-scale CRISPR-Cas9 screening data. P.A. Clemons performed analysis of small-molecule sensitivity profiling and RT-qPCR data. C.Y.L. and H.E.S. performed analysis of ChIP-sequencing and ATAC-sequencing data. S.S., F.H., P.C., and J.S. provided patient-derived tissue. T.Z., N.S.G., P.A. Clarke, J.B., P.W. provided small-molecule reagents and provided guidance on small-molecule sensitivity experiments. J.M.F. supervised RNA-sequencing studies. G.S.C., F.V., D.E.R., and W.C.H supervised genome-scale CRISPR-Cas9 screening studies. C.Y.L. and J.E.B. supervised ChIP-sequencing and ATAC-sequencing studies. K.K.W. supervised in vivo studies. T.S., M.J.W., P.A. Clemons, C.Y.L, J.D.K, and S.L.S. wrote and/or revised the manuscript. All authors reviewed and/or provided feedback on the manuscript.
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Descrição: Chordoma is a primary bone cancer with no approved therapy . The identification of therapeutic targets in this disease has been challenging due to the infrequent occurrence of clinically actionable somatic mutations in chordoma tumors . 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 . 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.
Editor: United States: Nature Publishing Group
Idioma: Inglês

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Small-molecule targeting of brachyury transcription factor addiction in chordoma

United States: Nature Publishing Group

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