Abstract
Synthetic lethality is a genetic phenomenon whereby the simultaneous presence of two different genetic alterations impairs cellular viability. Importantly, targeting synthetic lethal interactions offers potential therapeutic strategies for cancers with alterations in pathways that might otherwise be considered undruggable. High-throughput screening methods based on modern CRISPR–Cas9 technologies have emerged and become crucial for identifying novel synthetic lethal interactions with the potential for translation into biologically rational cancer therapeutic strategies as well as associated predictive biomarkers of response capable of guiding patient selection. Spurred by the clinical success of PARP inhibitors in patients with BRCA-mutant cancers, novel agents targeting multiple synthetic lethal interactions within DNA damage response pathways are in clinical development, and rational strategies targeting synthetic lethal interactions spanning alterations in epigenetic, metabolic and proliferative pathways have also emerged and are in late preclinical and/or early clinical testing. In this Review, we provide a comprehensive overview of established and emerging technologies for synthetic lethal drug discovery and development and discuss promising therapeutic strategies targeting such interactions.
Key points
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Clinically approved PARP inhibitors have provided proof-of-concept for the synthetic lethality approach by achieving successful outcomes in patients with cancer.
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Various hallmarks of cancer might be targetable using a synthetic lethal approach, including the DNA damage response, epigenetic alterations, and changes in cellular metabolism and proliferation.
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CRISPR–Cas9 technologies have led to the discovery of new druggable signalling pathways and synthetic lethal interactions in cell lines and to the development of novel drugs designed to target these interactions.
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Multiple novel antitumour therapeutics, including DNA damage response inhibitors, Werner helicase inhibitors, MTA-cooperative PRMT5 inhibitors, MAT2A inhibitors, SMARCA2 degraders, glutaminase inhibitors and enhancer of zeste homologue 2 (EZH2) inhibitors, are currently being tested in early phase trials, either as monotherapies or in combination with other agents.
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D.G. is an employee of and holds shares in Repare Therapeutics. D.D. holds shares in Repare Therapeutics and Induxion Therapeutics. T.A.Y. is an employee of the University of Texas MD Anderson Cancer Center as Vice President and Head of Clinical Development in the Therapeutics Discovery Division, which has a commercial interest in DDR and other inhibitors (for example IACS30380/ART0380 was licensed to Artios); has acted as a consultant of AbbVie, AstraZeneca, Acrivon, Adagene, Almac, Aduro, Amphista, Artios, Athena, Atrin, Avoro, Axiom, Baptist Health Systems, Bayer, Beigene, Boxer, Bristol Myers Squibb, C4 Therapeutics, Calithera, Cancer Research UK, Clovis, Cybrexa, Diffusion, EMD Serono, F-Star, Genmab, Glenmark, GLG, Globe Life Sciences, GSK, Guidepoint, Idience, Ignyta, I-Mab, ImmuneSensor, Impact, Institut Gustave Roussy, Intellisphere, Jansen, Kyn, MEI pharma, Mereo, Merck, Natera, Nexys, Novocure, OHSU, OncoSec, Ono Pharma, Pegascy, PER, Pfizer, Piper-Sandler, Prolynx, Repare, resTORbio, Roche, Schrodinger, Theragnostics, Varian, Versant, Vibliome, Xinthera, Zai Labs and ZielBio; is stockholder in Seagen; and has received institutional research funding from Acrivon, Artios, AstraZeneca, Bayer, Beigene, BioNTech, Blueprint, BMS, Clovis, Constellation, Cyteir, Eli Lilly, EMD Serono, Forbius, F-Star, Artios, GlaxoSmithKline, Genentech, Haihe, Ideaya, ImmuneSensor, Ionis, Ipsen, Jounce, Karyopharm, KSQ, Kyowa, Merck, Mirati, Novartis, Pfizer, Ribon Therapeutics, Regeneron, Repare, Rubius, Sanofi, Scholar Rock, Seattle Genetics, Tesaro, Vivace and Zenith. N.Y.L.N., C.T. and M.N. declare no competing interests.
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Ngoi, N.Y.L., Gallo, D., Torrado, C. et al. Synthetic lethal strategies for the development of cancer therapeutics. Nat Rev Clin Oncol 22, 46–64 (2025). https://doi.org/10.1038/s41571-024-00966-z
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DOI: https://doi.org/10.1038/s41571-024-00966-z
