Cell reports · 2026
Genome-wide CRISPR screens map synthetic lethal interactions across recurrent cancer driver alterations.
СтатьяНазвание и аннотация: Перевод в очереди
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Desjardins Jessica, Bowlan Julian, Bernier Cynthia, Jain Srishti, Goullet de Rugy Théo, Gallo David, Orcholski Mark E, Laterreur Nancy, Rajah Abira, Miller Joshua, Lafontaine Jennifer, Bhaskaran Vivek, Li Li, Ling Alexanda, Leblanc Jesse H, Mathieu Marie-Claude, Zinda Michael, Morris Stephen J, Durocher Daniel, Zimmermann Michal, Roulston Anne, Veloso Artur, Fiore Chris, Álvarez-Quilón Alejandro, Young Jordan T F
Аннотация
Synthetic lethality (SL) provides a treatment paradigm for targeting cancer with alterations in driver genes that are not conventionally druggable, including tumor suppressor genes. We execute a series of genome-wide CRISPR screens using functionally validated isogenic cell lines and conduct a large-scale SL analysis using data from the cancer dependency map (DepMap). We chart SL interactions across 15 driver alterations: FBXW7, CCNE1, CDK12, ARID1A, KMT2D, DNMT3A, TET2, KEAP1, STK11, IDH1, SF3B1, SRSF2, U2AF1, chromosome 18q loss, and chromosome 13q loss. We show validation of several SL interactions, including ARID1A and the hexosamine biosynthetic pathway aminotransferase GFPT1, STK11 with CAMK protein kinase MARK2, FBXW7 and the CDK1 regulatory kinase PKMYT1, and CCNE1 amplification and the anaphase-promoting complex or cyclosome (APC/C). In summary, this study offers a rich resource of genetic interactions across cancer drivers enabling the discovery of biological insights and drug targets for future therapeutic development.