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 11 December 2017

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Targeting oncogenes for esophageal squamous cell carcinoma therapy

The latest issue of Gut investigates super-enhancer-associated oncogenes in the treatment of esophageal squamous cell carcinoma.

News image

Esophageal squamous cell carcinoma is an aggressive malignancy and the major histological subtype of esophageal cancer.

Although recent large-scale genomic analysis has improved the description of the genetic abnormalities of esophageal squamous cell carcinoma, few targetable genomic lesions have been identified, and no molecular therapy is available.

Dr Yan-Yi Jiang and colleagues identified druggable candidates in this tumor.

High-throughput small-molecule inhibitor screening was performed to identify potent anti-esophageal squamous cell carcinoma compounds.

Whole-transcriptome sequencing and chromatin immunoprecipitation sequencing (ChIP-Seq) were conducted to decipher the mechanisms of action of CDK7 inhibition in esophageal squamous cell carcinoma.

Low-dose THZ1 treatment caused selective inhibition of a number of oncogenic transcripts
Gut

A variety of in vitro and in vivo cellular assays were performed to determine the effects of candidate genes on esophageal squamous cell carcinoma malignant phenotypes.

The team discoverd that the high-throughput small-molecule inhibitor screening led to a highly potent anti-esophageal squamous cell carcinoma compound, THZ1, a specific CDK7 inhibitor.

Whole-transcriptome sequencing revealed that low-dose THZ1 treatment caused selective inhibition of a number of oncogenic transcripts.

The researchers found that further characterisation of the genomic features of these THZ1-sensitive transcripts demonstrated that they were frequently associated with super-enhancer.

The team noted that super-enhancer analysis alone uncovered many esophageal squamous cell carcinoma lineage-specific master regulators.

Finally, integrative analysis of both THZ1-sensitive and super-enhancer-associated transcripts identified a number of novel esophageal squamous cell carcinoma oncogenes, including PAK4, RUNX1, DNAJB1, SREBF2 and YAP1, with PAK4 being a potential druggable kinase.

Dr Jiang's team comments, "Our integrative approaches led to a catalogue of SE-associated master regulators and oncogenic transcripts, which may significantly promote both the understanding of esophageal squamous cell carcinoma biology and the development of more innovative therapies."

Gut 2017;66:1358-1368
20 July 2017

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