Jessica Desjardins, Julian Bowlan, Cynthia Bernier, Srishti Jain, Théo Goullet de Rugy, David Gallo, Mark E Orcholski, Nancy Laterreur, Abira Rajah, Joshua Miller, Jennifer Lafontaine, Vivek Bhaskaran, Li Li, Alexanda Ling, Jesse H Leblanc, Marie-Claude Mathieu, Michael Zinda, Stephen J Morris, Daniel Durocher, Michal Zimmermann, Anne Roulston, Artur Veloso, Chris Fiore, Alejandro Álvarez-Quilón, Jordan T F Young
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.