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Updated: May 12, 2026
07:40
A Data Integration Workflow to Identify Drug Combinations Targeting Synthetic Lethal Interactions
Published on: May 27, 2021
An evolutionarily conserved synthetic lethal interaction network identifies FEN1 as a broad-spectrum target for
Derek M van Pel1, Irene J Barrett, Yoko Shimizu
1Michael Smith Laboratories, University of British Columbia, Vancouver, Canada.
Plos Genetics
|February 6, 2013
Summary
Researchers identified potential cancer drug targets by studying genetic differences between cancer and normal cells. They found that inhibiting flap endonuclease FEN1 selectively killed cancer cells with specific mutations, showing promise for new cancer therapies.
Area of Science:
- Genetics
- Molecular Biology
- Cancer Research
Background:
- Targeting genetic differences between cancer and normal cells is a promising therapeutic strategy.
- Chromosome instability (CIN) genes are frequently mutated in colorectal cancer.
Purpose of the Study:
- To construct and evaluate a synthetic lethal interaction network of CIN genes in human cells.
- To identify novel therapeutic targets for colorectal cancer.
Main Methods:
- Utilized yeast genetic interaction data to inform human cell experiments.
- Employed siRNA to build a synthetic lethal interaction network.
- Screened for small-molecule inhibitors of flap endonuclease FEN1 using a fluorescence-based assay.
Main Results:
- Identified a subset of genes with synthetic lethal interactions with numerous cancer CIN genes.
- Discovered two compounds that selectively inhibit the proliferation of cancer cells with CDC4 mutations.
- Demonstrated that inhibiting FEN1 recapitulates synthetic lethality with MRE11A and increases DNA damage.
Conclusions:
- A cross-species approach successfully identified evolutionarily conserved synthetic lethal interactions.
- Small-molecule inhibitors targeting FEN1 show efficacy in a cell-based cancer model.
- This strategy validates the use of synthetic lethality for anticancer drug development.
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