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Updated: May 15, 2025
A Data Integration Workflow to Identify Drug Combinations Targeting Synthetic Lethal Interactions
Published on: May 27, 2021
Synthetic lethality in cancer: a protocol for scoping review of gene interactions from synthetic lethal screens and
Raashi Chauhan1, Rama Rao Damerla2, Vijay Shree Dhyani3
1Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, India.
Background:
Two genes are synthetically lethal if loss of function of either one of the two genes does not result in cell death, whereas loss of function of both genes together results in being detrimental to cell survival. This concept has been the basis for developing personalized, precision treatments, which can selectively damage tumor cells and minimize toxicity to normal tissues. Tumor cells often harbor mutations in genes involved in DNA repair pathways, forcing them to switch to alternative repair pathways, leading to chemotherapeutic resistance. These interactions, if targeted, could be synthetically lethal. We aimed to summarize synthetically lethal gene pairs that could be utilized to selectively target cancer cells and minimize side effects on normal tissues. The objective of this review is to study druggable synthetically lethal gene pairs for targeted cancer therapy that have been identified through various genetic screens and functional studies.
Methods:
A systematic literature search will be conducted to extract synthetically lethal gene pairs that can be specifically targeted to cancer cells. Owing to the relatively recent research pertaining to this field, the literature search will incorporate data from 1956. The search will be conducted on PubMed, Web of Science, Embase, and Scopus. The narrative approach will guide the analysis and synthesis of the results.
Discussion:
This review highlights scientific articles that report druggable synthetically lethal gene pairs by testing the efficacy of targeted inhibitors in clonogenic assays. These include research studies that identify synthetically lethal gene pairs detected through CRISPR screens by knocking out one or two genes within the same cell and testing the potency of inhibitors to specifically kill malignant cells.
Systematic Review Registration:
https://doi.org/10.17605/OSF.IO/5BCW6 .
Insights
Synthetically lethal gene pairs offer a promising strategy for precision cancer therapy. Targeting these pairs can selectively eliminate tumor cells while sparing healthy tissues, minimizing treatment side effects.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Synthetic lethality involves gene pairs where loss of either gene is tolerated, but loss of both is lethal.
- Cancer cells often exploit alternative DNA repair pathways due to mutations, creating vulnerabilities.
- Targeting these vulnerabilities offers a route to selective cancer cell killing.
Purpose of the Study:
- To review and summarize druggable synthetically lethal gene pairs for targeted cancer therapy.
- To identify gene pairs that can be exploited for precision medicine approaches.
- To consolidate findings from genetic screens and functional studies.
Main Methods:
- Systematic literature search across major databases (PubMed, Web of Science, Embase, Scopus).
- Inclusion of studies from 1956 to present, employing a narrative review approach.
- Analysis of research identifying synthetically lethal pairs through CRISPR screens and inhibitor efficacy testing.
Main Results:
- Highlighting scientific articles reporting druggable synthetically lethal gene pairs.
- Focus on studies testing targeted inhibitors in clonogenic assays.
- Identification of gene pairs through gene knockout screens and subsequent inhibitor potency evaluation.
Conclusions:
- Synthetically lethal gene pairs represent a viable strategy for developing targeted cancer therapies.
- This approach holds potential for increasing treatment efficacy and reducing toxicity.
- Further research into druggable synthetic lethal interactions is crucial for advancing precision oncology.
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