The SCHEMATIC resource combines CRISPR pairwise gene knockout experiments across tumor cell types with large-scale drug sensitivity assays to identify a core network of highly penetrant, synthetic lethal genetic interactions that can help to match individuals with cancer to targeted therapies.
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References
Hartwell, L. H., Szankasi, P., Roberts, C. J., Murray, A. W. & Friend, S. H. Integrating genetic approaches into the discovery of anticancer drugs. Science 278, 1064–1068 (1997). A landmark review that describes how synthetic lethal interactions can help the design of anticancer drugs.
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Ryan, C. J., Bajrami, I. & Lord, C. J. Synthetic lethality and cancer—penetrance as the major barrier. Trends Cancer Res. 4, 671–683 (2018). A perspective postulating that many synthetic lethal interactions are not penetrant across cancer contexts.
Yang, W. et al. Genomics of Drug Sensitivity in Cancer (GDSC): a resource for therapeutic biomarker discovery in cancer cells. Nucleic Acids Res. 41, D955–61 (2013). This article describes the GDSC resource that we used to corroborate synthetic lethal interactions discovered in combinatorial CRISPR screens.
Gozgit, J. M. et al. PARP7 negatively regulates the type I interferon response in cancer cells and its inhibition triggers antitumor immunity. Cancer Cell 39, 1214–1226.e10 (2021). This article explores a PARP7 small-molecule inhibitor, which our study shows is particularly effective against tumor cells with genetic alterations in KDM genes.
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This is a summary of: Fong, S. H. et al. A multilineage screen identifies actionable synthetic lethal interactions in human cancers. Nat. Genet. https://doi.org/10.1038/s41588-024-01971-9 (2024).
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A blueprint to discovering synthetic lethal gene interactions for precision oncology. Nat Genet 57, 9–10 (2025). https://doi.org/10.1038/s41588-024-02024-x
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DOI: https://doi.org/10.1038/s41588-024-02024-x
