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A Data Integration Workflow to Identify Drug Combinations Targeting Synthetic Lethal Interactions
Published on: May 27, 2021
Synthetic Lethality in Cancer Therapeutics: The Next Generation
Jeremy Setton1, Michael Zinda2, Nadeem Riaz1
1Memorial Sloan Kettering Cancer Center, New York, New York.
Abstract:
Synthetic lethality (SL) provides a conceptual framework for tackling targets that are not classically "druggable," including loss-of-function mutations in tumor suppressor genes required for carcinogenesis. Recent technological advances have led to an inflection point in our understanding of genetic interaction networks and ability to identify a wide array of novel SL drug targets. Here, we review concepts and lessons emerging from first-generation trials aimed at testing SL drugs, discuss how the nature of the targeted lesion can influence therapeutic outcomes, and highlight the need to develop clinical biomarkers distinct from those based on the paradigms developed to target activated oncogenes. SIGNIFICANCE: SL offers an approach for the targeting of loss of function of tumor suppressor and DNA repair genes, as well as of amplification and/or overexpression of genes that cannot be targeted directly. A next generation of tumor-specific alterations targetable through SL has emerged from high-throughput CRISPR technology, heralding not only new opportunities for drug development, but also important challenges in the development of optimal predictive biomarkers.
Insights
Synthetic lethality (SL) offers a new strategy to target previously undruggable cancer genes, including those with loss-of-function mutations. Advances in genetic screening are identifying novel SL targets and driving the development of new cancer therapies.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- Synthetic lethality (SL) provides a framework for targeting genes not amenable to traditional drug development, particularly tumor suppressor genes with loss-of-function mutations.
- Technological advancements are rapidly expanding the understanding of genetic interaction networks and identifying novel SL drug targets.
Purpose of the Study:
- To review current concepts and lessons from early-phase clinical trials of SL drugs.
- To discuss the impact of lesion type on therapeutic outcomes.
- To emphasize the need for novel clinical biomarkers for SL-targeted therapies.
Main Methods:
- Review of first-generation clinical trials testing synthetic lethality drugs.
- Analysis of how the nature of the targeted genetic lesion influences therapeutic efficacy.
- Identification of emerging challenges in biomarker development for synthetic lethality approaches.
Main Results:
- Synthetic lethality enables targeting of loss-of-function tumor suppressor and DNA repair genes, as well as amplified or overexpressed genes.
- High-throughput CRISPR screening is revealing a new generation of tumor-specific alterations targetable via synthetic lethality.
Conclusions:
- Synthetic lethality presents a promising avenue for developing therapies against previously intractable cancer targets.
- Development of predictive biomarkers distinct from those for oncogene-targeted therapies is crucial for clinical success.
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