Regulatory enhancer profiling of mesenchymal-type gastric cancer reveals subtype-specific epigenomic landscapes and targetable vulnerabilities (Gut, Jul 2022)

According to GLOBOCAN, gastric cancer (GC) is a significant cause of cancer mortality worldwide, with over 700,000 deaths attributable to it annually. Mesenchymal-subtype gastric cancer (Mes-GC) is a particularly aggressive subtype associated with poor clinical prognosis and chemoresistance. However, few effective treatment options are currently available. Existing regimens consist of “one-size-fits-all” approaches such as surgery and chemo/radiotherapy, which offer poor 5-year survival rates below 30%. While studies have identified specific biomarkers for precision GC treatment over the past decade, there remains a lack of targeted treatment available for Mes-GCs.

To combat this issue, Dr. Shamaine Ho Wei Ting, a recent graduate of CSI Singapore’s PhD Programme, under the mentorship of Prof. Patrick Tan, Senior Principal Investigator at CSI Singapore and Professor of Cancer and Stem Cell Biology at Duke-NUS Medical School, led a team of researchers in first consolidating previous studies on Mes-GCs to identify and validate a robust consensus 993-gene Mes-GC classifier. Their findings were published in the reputable journal Gut, on 03 June 2022.

Based on the analysis of over 1000 GCs and cell lines, the researchers demonstrated that their identified Mes-GC classifier is easily reproducible, applicable to both microarray and RNA-seq datasets, and can be used to classify both retrospective and prospective cohorts. They also discovered that Mes-GCs exhibit a distinctive epigenomic landscape, with TEAD1 as a master regulator of Mes-GC enhancers and Mes-GCs exhibiting preferential sensitivity to TEAD1 pharmacological inhibition. NUAK1 kinase was also highlighted as a downstream target of Mes-GC super-enhancers, with synergistic effects observed between NUAK1 inhibition and cisplatin treatment.

The results of this study not only offer a standardised manner to better identify Mes-GCs in different transcriptomic scenarios, but also lay the foundation for future genomics-based investigations, such as functional CRISPR screening that can further elucidate distinct disease mechanisms. Furthermore, the team’s findings also establish TEAD1 inhibition and combinatorial NUAK1 inhibition with cisplatin as potential targeted therapies for highly lethal Mes-GCs that currently suffer from a dearth of effective treatments.

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