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A Data Integration Workflow to Identify Drug Combinations Targeting Synthetic Lethal Interactions
Published on: May 27, 2021
A high-throughput screen to identify novel synthetic lethal compounds for the treatment of E-cadherin-deficient cells
Henry Beetham1, Augustine Chen1, Bryony J Telford1
1Cancer Genetics Laboratory, Department of Biochemistry, University of Otago, Dunedin, New Zealand.
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.
Insights
Researchers identified new compounds that kill cancer cells lacking E-cadherin (CDH1). This synthetic lethality approach offers a potential new treatment strategy for diffuse gastric cancer and lobular breast cancer.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- E-cadherin (CDH1) is a crucial tumor suppressor maintaining cell adhesion, polarity, and survival.
- Somatic and germline mutations in CDH1 are prevalent in diffuse gastric cancer (DGC), lobular breast cancer (LBC), and Hereditary Diffuse Gastric Cancer (HDGC).
- Targeting tumor suppressor gene mutations via synthetic lethality presents a promising therapeutic avenue.
Purpose of the Study:
- To discover novel synthetic lethal compounds effective against E-cadherin-deficient (CDH1-mutated) cancers.
- To identify druggable vulnerabilities arising from E-cadherin loss in tumor cells.
Main Methods:
- Conducted a high-throughput screening of approximately 114,000 lead-like compounds.
- Utilized an isogenic pair of human mammary epithelial cell lines (with and without CDH1 expression).
- Validated identified compounds using real-time and end-point viability assays.
Main Results:
- Identified 12 novel compounds that selectively harmed E-cadherin-deficient cells.
- Validated two compounds demonstrating significant synthetic lethal activity.
- Confirmed that E-cadherin loss creates exploitable vulnerabilities in cancer cells.
Conclusions:
- Novel synthetic lethal compounds targeting E-cadherin loss have been identified.
- These compounds represent a potential new therapeutic strategy for sporadic and hereditary LBC and DGC.
- Further development may lead to new treatments for cancers with CDH1 mutations.
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