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Updated: Mar 29, 2026
Dual CRISPR-Interference Strategy for Targeting Synthetic Lethal Interactions Between Non-Coding RNAs in Cancer Cells
Published on: May 30, 2025
Current views on inducing synthetic lethal RNAi responses in the treatment of cancer
Apollo D Kacsinta1, Steven F Dowdy1
1a Department of Cellular and Molecular Medicine , UCSD School of Medicine , La Jolla , CA , USA.
Introduction:
Cancer cells arise from normal cells that have incurred mutations in oncogenes and tumor suppressor genes. The mutations are often unique and not readily found in normal cells, giving rise to the opportunity of exploiting these mutations to induce synthetic lethality. Synthetic lethality occurs when inhibition or mutation in two or more separate genes leads to cell death while inhibition or mutations of either gene alone has no lethal effect on the cell. Using RNA interference (RNAi) to identify synthetic lethality has become a growingly popular screening approach.
Areas Covered:
In this review, we cover the use of RNAi therapeutics to induce synthetic lethality in cancer. Additionally, we discuss several select small molecule inhibitors that were identified or verified by RNAi that induce synthetic lethality in specific cancers. We also discuss the identification of novel synthetic lethal combinations and the cancer model that the combination was validated in. Lastly, we discuss RNAi delivery vehicles.
Expert Opinion:
While RNAi therapeutics have great potential to treat cancer, due to the siRNA delivery problem, RNAi remains more commonly used as a tool, rather than a therapeutic. However, with emerging technological advances in the field of RNAi therapeutics, it is only a matter of time before RNAi-induced synthetic lethal clinical studies are initiated in cancer patients.
Insights
Cancer cells with unique mutations can be targeted using RNA interference (RNAi) to induce synthetic lethality. This approach exploits gene interactions to kill cancer cells, with ongoing advancements paving the way for clinical applications.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Cancer develops from normal cells with mutations in oncogenes and tumor suppressor genes.
- These unique mutations offer therapeutic targets for synthetic lethality.
- Synthetic lethality involves the combined effect of inhibiting or mutating two or more genes, leading to cell death.
Purpose of the Study:
- To review the application of RNA interference (RNAi) therapeutics for inducing synthetic lethality in cancer.
- To discuss small molecule inhibitors identified or verified by RNAi for specific cancers.
- To explore novel synthetic lethal combinations and their validation in cancer models.
Main Methods:
- Review of RNA interference (RNAi) as a screening approach for synthetic lethality.
- Discussion of small molecule inhibitors identified through RNAi.
- Examination of novel synthetic lethal combinations and cancer models.
- Analysis of RNAi delivery vehicles.
Main Results:
- RNA interference is a popular screening method for identifying synthetic lethal interactions.
- Several small molecule inhibitors verified by RNAi demonstrate synthetic lethality in specific cancers.
- Novel synthetic lethal combinations have been identified and validated in various cancer models.
Conclusions:
- RNAi therapeutics hold significant potential for cancer treatment.
- The delivery of small interfering RNA (siRNA) remains a challenge, limiting current therapeutic use.
- Technological advancements are expected to enable clinical studies of RNAi-induced synthetic lethality in cancer patients.
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