A high-throughput screen to identify novel synthetic lethal compounds for the treatment of E-cadherin-deficient cells
- Author(s)
- Beetham, H; Chen, A; Telford, BJ; Single, A; Jarman, KE; Lackovic, K; Luxenburger, A; Guilford, P;
- Details
- Publication Year 2019-08-29,Volume 9,Issue #1,Page 12511
- Journal Title
- Scientific Reports
- Publication Type
- Journal Article
- 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.
- Publisher
- Springer Nature
- Research Division(s)
- Advanced Technology And Biology
- PubMed ID
- 31467357
- Publisher's Version
- https://doi.org/10.1038/s41598-019-48929-0
- Open Access at Publisher's Site
https://doi.org/10.1038/s41598-019-48929-0- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2019-09-20 10:16:27
Last Modified: 2019-09-24 03:10:13