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Small-molecule targeting of brachyury transcription factor addiction in chordoma [ChIP-Seq]

ABSTRACT: 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 (TFs). 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 TF. Strikingly, transcriptional CDK inhibition leads to preferential and concentration-dependent downregulation of cellular brachyury protein levels in all models tested. Together, these data demonstrate small-molecule targeting of brachyury TF 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE109791 | GEO | 2019/01/20

REPOSITORIES: GEO

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Small-molecule targeting of brachyury transcription factor addiction in chordoma [ATAC-Seq]

Project description: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 (TFs). 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 TF. Strikingly, transcriptional CDK inhibition leads to preferential and concentration-dependent downregulation of cellular brachyury protein levels in all models tested. Together, these data demonstrate small-molecule targeting of brachyury TF 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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Targeted brachyury degradation disrupts a highly specific autoregulatory program controlling chordoma cell identity [Total RNA-seq, SLAM-seq]

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Brachyury ChIP sequencing of human chordoma UCH-1 cell line

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Receptor Tyrosine Kinase pathway activation is sufficient to trigger chordoma in zebrafish

Project description:Oncogenic transformation of individual cell fates by developmental signaling cascades and transcription factors triggers diverse cancer types. Chordoma is a rare, aggressive tumor arising from transformed notochord remnants. Various potentially oncogenic factors have been found deregulated in chordoma and its metastases, yet clear causation remains uncertain. In particular, expression of the notochord-controlling transcription factor Brachyury is hypothesized as key molecular driver in chordoma formation, yet an in vivo model to causally test its oncogenic potential in the notochord is missing. Here, we apply a zebrafish model of chordoma onset to identify the notochord-transforming potential of tumor-implicated candidate genes in vivo. We find that overexpression of human and zebrafish Brachyury, including a version with augmented transcriptional activity, is insufficient to initiate notochord hyperplasia in vivo. In contrast, the repeatedly chordoma-implicated receptor tyrosine kinase (RTK) genes EGFR and KDR/VEGFR2 are sufficient to transform developmental notochord cells, akin to direct activation of Ras. Analysis of transcriptome and sub-cellular organization from transformed notochords suggests that aberrant activation of RTK/Ras signaling attenuates processes required for the differentiation of notochord cells. Taken together, our results provide first in vivo indication for a lack of tumor-initiating potential of Brachyury expression in the notochord, and suggest activated RTK signaling as potent hyperplasia-initiating event in chordoma.

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Project description:Identifying the spectrum of genes required for cancer cell survival can reveal essential cancer circuitry and therapeutic targets, but such a map remains incomplete for many cancer types. We apply genome-scale CRISPR-Cas9 loss-of-function screens to map the landscape of selectively essential genes in chordoma, a bone cancer with few validated targets. This approach confirms a known chordoma dependency, TBXT (T; brachyury), and identifies a range of additional dependencies, including PTPN11, ADAR, PRKRA, LUC7L2, SRRM2, SLC2A1, SLC7A5, FANCM, and THAP1. CDK6, SOX9, and EGFR, genes previously implicated in chordoma biology, are also recovered. We find genomic and transcriptomic features that predict specific dependencies, including interferon-stimulated gene expression, which correlates with ADAR dependence and is elevated in chordoma. Validating the therapeutic relevance of dependencies, small-molecule inhibitors of SHP2, encoded by PTPN11, have potent preclinical efficacy against chordoma. Our results generate an emerging map of chordoma dependencies to enable biological and therapeutic hypotheses.

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