Small-molecule targeting of brachyury transcription factor addiction in chordoma.

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 tumors^2,3. 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 t

SUBMITTER: Sharifnia T 

PROVIDER: S-EPMC6633917 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature