2. Academic Validation
  3. Small-molecule targeting of brachyury transcription factor addiction in chordoma

Small-molecule targeting of brachyury transcription factor addiction in chordoma

  • Nat Med. 2019 Feb;25(2):292-300. doi: 10.1038/s41591-018-0312-3.
Tanaz Sharifnia 1,  Mathias J Wawer 2,  Ting Chen 3,  Qing-Yuan Huang 3 4,  Barbara A Weir 2 5,  Ann Sizemore 2 6,  Matthew A Lawlor 7 8,  Amy Goodale 2,  Glenn S Cowley 2 9,  Francisca Vazquez 2,  Christopher J Ott 7 8,  Joshua M Francis 2 10,  Slim Sassi 11 12,  Patricia Cogswell 13,  Hadley E Sheppard 14,  Tinghu Zhang 7,  Nathanael S Gray 7,  Paul A Clarke 15,  Julian Blagg 15,  Paul Workman 15,  Josh Sommer 13,  Francis Hornicek 11 16,  David E Root 2,  William C Hahn 2 7,  James E Bradner 7 17,  Kwok K Wong 3,  Paul A Clemons 2,  Charles Y Lin 18,  Joanne D Kotz 19 20,  Stuart L Schreiber 21 22 23
Affiliations

Affiliations

  • 1 Broad Institute of Harvard and MIT, Cambridge, MA, USA. [email protected].
  • 2 Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • 3 New York University Langone Medical Center, New York, NY, USA.
  • 4 Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China.
  • 5 Janssen R&D, Cambridge, MA, USA.
  • 6 University of Pennsylvania, Philadelphia, PA, USA.
  • 7 Dana-Farber Cancer Institute, Boston, MA, USA.
  • 8 Massachusetts General Hospital, Charlestown, MA, USA.
  • 9 Janssen R&D, Spring House, PA, USA.
  • 10 Gritstone Oncology, Cambridge, MA, USA.
  • 11 Massachusetts General Hospital, Boston, MA, USA.
  • 12 Harvard Medical School, Boston, MA, USA.
  • 13 Chordoma Foundation, Durham, NC, USA.
  • 14 Baylor College of Medicine, Houston, TX, USA.
  • 15 Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, UK.
  • 16 UCLA Medical Center, Santa Monica, CA, USA.
  • 17 Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
  • 18 Baylor College of Medicine, Houston, TX, USA. [email protected].
  • 19 Broad Institute of Harvard and MIT, Cambridge, MA, USA. [email protected].
  • 20 Jnana Therapeutics, Boston, MA, USA. [email protected].
  • 21 Broad Institute of Harvard and MIT, Cambridge, MA, USA. [email protected].
  • 22 Harvard University, Cambridge, MA, USA. [email protected].
  • 23 Howard Hughes Medical Institute, Chevy Chase, MD, USA. [email protected].
PMID: 30664779 DOI: 10.1038/s41591-018-0312-3
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.

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