In a letter published on 21 January 2019 in the Nature Medicine, Tanaz Sharifnia and Stuart L. Schreiber of the Broad Institute of Harvard and MIT, Cambridge, MA, USA and colleagues described discovery of therapeutically targetable chordoma dependencies via genome-scale CRISPR-Cas9 screening and focused small-molecule sensitivity profiling. Identification of therapeutic targets in chordoma has been challenging so far, due to the infrequent occurrence of clinically actionable somatic mutations. The latest study revealed that the developmental transcription factor T (brachyury; TBXT) is the top selectively essential gene in chordoma.
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, the study investigators found 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 led to preferential and concentration-dependent downregulation of cellular brachyury protein levels in all models tested. In vivo, CDK7/12/13-inhibitor treatment substantially reduced tumour growth.
The study team concluded that 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.
Computational code used for ChIP-seq analysis can be found here. Code for CRISPR-Cas9 screening analysis is available on GParc. Code for small-molecule sensitivity profiling analysis and DNA and RNA-sequencing analysis are available upon reasonable request.
This study was supported by the Chordoma Foundation, the Roye family, the Fuchs family and the US NCI’s Cancer Target Discovery and Development Network grants. In addition, support was provided by the Cancer Prevention Research Institute of Texas and by the NIH and NCI, and a Pew-Stewart Scholarship for Cancer Research (Alexander and Margaret Stewart Trust). The Institute of Cancer Research authors were funded by Cancer Research UK grant and fellowship.
Sharifnia T, Wawer MJ, Chen T, et al. Small-molecule targeting of brachyury transcription factor addiction in chordoma. Nature Medicine; Published online 21 January 2019. doi: 10.1038/s41591-018-0312-3.