CDK7 is a novel therapeutic vulnerability in Fibrolamellar cancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA971878 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24520200_1.fastq.gz | Fastqsanger.gz | |||
| SRR24520200_2.fastq.gz | Fastqsanger.gz | |||
| SRR24520201_1.fastq.gz | Fastqsanger.gz | |||
| SRR24520201_2.fastq.gz | Fastqsanger.gz | |||
| SRR24520190_1.fastq.gz | Fastqsanger.gz |
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Project description:Anaplastic thyroid carcinoma (ATC) is one of the most aggressive malignancy and accounts for the majority of thyroid cancer-related deaths. Despite intensive research, there remains no effective treatment for patients with ATC. Here, we identify THZ1, a covalent inhibitor of cyclin-dependent kinase 7 (CDK7), as a potent anti-ATC compound by high-throughput chemical screening. ATC cells, but not papillary thyroid cancer (PTC) cells, are exceptionally sensitive to CDK7 inhibition. Analyzing both gene expression profiles and super enhancer (SE) features reveals that the SE-mediated oncogenic transcriptional amplification renders the vulnerability of ATC cells to THZ1 treatment. Combining this integrative analysis with functional assays discovers a number of novel cancer genes of ATC, including PPP1R15A, SMG9 and KLF2. Inhibition of PPP1R15A with Guanabenz (GBZ) or Sephin1 greatly suppresses ATC growth. Significantly, the expression level of PPP1R15A is correlated with CDK7 expression in ATC tissue samples. Elevated expression of PPP1R15A and CDK7 are both associated with poor clinical prognosis in ATC patients. Importantly, GBZ or THZ1 treatment sensitizes ATC cells to conventional chemotherapy. Taken together, these findings demonstrate transcriptional addiction in ATC pathobiology and identify CDK7 and PPP1R15A as potential biomarkers and therapeutic targets for ATC.
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