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Published on: May 21, 2018
A Data Integration Workflow to Identify Drug Combinations Targeting Synthetic Lethal Interactions
Maximilian Marhold1, Andreas Heinzel2, Almas Merchant1
1Department of Internal Medicine I - Division of Oncology, Comprehensive Cancer Center, Medical University of Vienna.
Abstract:
A synthetic lethal interaction between two genes is given when knock-out of either one of the two genes does not affect cell viability but knock-out of both synthetic lethal interactors leads to loss of cell viability or cell death. The best studied synthetic lethal interaction is between BRCA1/2 and PARP1, with PARP1 inhibitors being used in clinical practice to treat patients with BRCA1/2 mutated tumors. Large genetic screens in model organisms but also in haploid human cell lines have led to the identification of numerous additional synthetic lethal interaction pairs, all being potential targets of interest in the development of novel tumor therapies. One approach is to therapeutically target genes with a synthetic lethal interactor that is mutated or significantly downregulated in the tumor of interest. A second approach is to formulate drug combinations addressing synthetic lethal interactions. In this article, we outline a data integration workflow to evaluate and identify drug combinations targeting synthetic lethal interactions. We make use of available datasets on synthetic lethal interaction pairs, homology mapping resources, drug-target links from dedicated databases, as well as information on drugs being investigated in clinical trials in the disease area of interest. We further highlight key findings of two recent studies of our group on drug combination assessment in the context of ovarian and breast cancer.
Insights
Synthetic lethal interactions offer new cancer therapy targets. This study presents a data integration workflow to identify effective drug combinations for targeting these interactions, with applications in ovarian and breast cancer.
Area of Science:
- Genomics
- Cancer Biology
- Pharmacology
Background:
- Synthetic lethality occurs when the combined loss of two genes leads to cell death, unlike the loss of either gene alone.
- The BRCA1/2 and PARP1 interaction is a clinically validated example, with PARP1 inhibitors used for BRCA1/2-mutated cancers.
- Numerous synthetic lethal pairs have been identified, presenting opportunities for novel cancer therapeutics.
Purpose of the Study:
- To outline a data integration workflow for evaluating and identifying drug combinations targeting synthetic lethal interactions.
- To leverage existing datasets for drug combination discovery in cancer therapy.
- To assess drug combinations in the context of ovarian and breast cancer.
Main Methods:
- Data integration of synthetic lethal interaction pairs, gene homology, drug-target links, and clinical trial information.
- Utilizing dedicated databases for drug and target information.
- Applying the workflow to assess drug combinations for ovarian and breast cancer.
Main Results:
- The study outlines a comprehensive workflow for identifying potential drug combinations based on synthetic lethality.
- Key findings from recent studies on drug combination assessment in ovarian and breast cancer are highlighted.
- The workflow integrates diverse biological and pharmacological data for robust evaluation.
Conclusions:
- Synthetic lethal interactions represent a promising avenue for developing targeted cancer therapies.
- The presented data integration workflow facilitates the identification of novel drug combinations for cancer treatment.
- This approach has potential applications in precision medicine for ovarian and breast cancer.
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