Abstract
The concept of synthetic lethality has been widely applied to identify therapeutic targets in cancer, with varying degrees of success. The standard approach normally involves identifying genetic interactions between two genes, a driver and a target. In reality, however, most cancer synthetic lethal effects are likely complex and also polygenic, being influenced by the environment in addition to involving contributions from multiple genes. By acknowledging and delineating this complexity, we describe in this article how the success rate in cancer drug discovery and development could be improved.
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Acknowledgements
We thank C. Astier for initial conversations regarding this article. We also thank the following for funding work in our respective laboratories: C.J.L. and S.J.P. thank Breast Cancer Now as part of program funding to the Breast Cancer Now Toby Robins Research Centre, Cancer Research UK as part of a program grant and the Basser Foundation. C.J.R. thanks the Science Foundation for funding under grant number 20/FFP-P/8641. Figures were generated using BioRender.
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The concept for this article was conceived by C.J.L. and C.J.R. The article and figures were written and compiled by C.J.L., C.J.R., L.P.S.D. and S.J.P.
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C.J.L. makes the following disclosures: he receives and/or has received research funding from AstraZeneca, Merck and Artios; he received consultancy, SAB membership or honoraria payments from Syncona, Sun Pharma, Gerson Lehrman Group, Merck, Vertex, AstraZeneca, Tango, Third Rock, Ono Pharma, Artios, Abingworth, Tesselate, Dark Blue Therapeutics, Pontifax, Astex, NeoPhore and GlaxoSmithKline; he has stock in Tango, Ovibio, Hysplex and Tesselate. C.J.L. is also a named inventor on patents describing the use of DNA-repair inhibitors and stands to gain from their development and use as part of the ICR ‘Rewards to Inventors’ scheme and also reports benefits from this scheme associated with patents for PARPi paid into C.J.L.’s personal account and research accounts at the Institute of Cancer Research. C.J.R., L.P.S.D. and S.J.P. have no competing interests to declare.
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Ryan, C.J., Devakumar, L.P.S., Pettitt, S.J. et al. Complex synthetic lethality in cancer. Nat Genet 55, 2039–2048 (2023). https://doi.org/10.1038/s41588-023-01557-x
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DOI: https://doi.org/10.1038/s41588-023-01557-x
