ArticleScientific reports2019
A high-throughput screen to identify novel synthetic lethal compounds for the treatment of E-cadherin-deficient cells.
Article in Scientific reports, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed, 13 citations in OpenAlex.
- Current advances in understanding the molecular profile of hereditary diffuse gastric cancer and its clinical implications.Journal of experimental & clinical cancer research : CR · 2023Review
- Hereditary Diffuse Gastric Cancer: A 2022 Update.Journal of personalized medicine · 2022Review
- Loss of Integrin-Linked Kinase Sensitizes Breast Cancer to SRC Inhibitors.Cancer research · 2022Article
- Loss of E-Cadherin Leads to Druggable Vulnerabilities in Sphingolipid Metabolism and Vesicle Trafficking.Cancers · 2021Article
- MCP mediated active targeting calcium phosphate hybrid nanoparticles for the treatment of orthotopic drug-resistant colon cancer.Journal of nanobiotechnology · 2021Article
- Natural products targeting cancer cell dependency.The Journal of antibiotics · 2021Review
- Synthetic Lethality through the Lens of Medicinal Chemistry.Journal of medicinal chemistry · 2020Review
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The cell-cell adhesion protein E-cadherin (CDH1) is a tumor suppressor that is required to maintain cell adhesion, cell polarity and cell survival signalling. Somatic mutations in CDH1 are common in diffuse gastric cancer (DGC) and lobular breast cancer (LBC). In addition, germline mutations in CDH1 predispose to the autosomal dominant cancer syndrome Hereditary Diffuse Gastric Cancer (HDGC). One approach to target cells with mutations in specific tumor suppressor genes is synthetic lethality. To identify novel synthetic lethal compounds for the treatment of cancers associated with E-cadherin loss, we have undertaken a high-throughput screening campaign of ~114,000 lead-like compounds on an isogenic pair of human mammary epithelial cell lines - with and without CDH1 expression. This unbiased approach identified 12 novel compounds that preferentially harmed E-cadherin-deficient cells. Validation of these compounds using both real-time and end-point viability assays identified two novel compounds with significant synthetic lethal activity, thereby demonstrating that E-cadherin loss creates druggable vulnerabilities within tumor cells. In summary, we have identified novel synthetic lethal compounds that may provide a new strategy for the prevention and treatment of both sporadic and hereditary LBC and DGC.
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Registered trials
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