Genome-wide CRISPR screens map synthetic lethal interactions across recurrent cancer driver alterations

  • Cell Rep. 2026 Sep 22;45(9):117961. doi: 10.1016/j.celrep.2026.117961.
Jessica Desjardins  1 ,  Julian Bowlan  2 ,  Cynthia Bernier  1 ,  Srishti Jain  1 ,  Théo Goullet de Rugy  1 ,  David Gallo  3 ,  Mark E Orcholski  1 ,  Nancy Laterreur  1 ,  Abira Rajah  1 ,  Joshua Miller  1 ,  Jennifer Lafontaine  1 ,  Vivek Bhaskaran  1 ,  Li Li  1 ,  Alexanda Ling  1 ,  Jesse H Leblanc  1 ,  Marie-Claude Mathieu  1 ,  Michael Zinda  2 ,  Stephen J Morris  1 ,  Daniel Durocher  4 ,  Michal Zimmermann  1 ,  Anne Roulston  1 ,  Artur Veloso  2 ,  Chris Fiore  2 ,  Alejandro Álvarez-Quilón  5 ,  Jordan T F Young  6
Affiliations
  • 1. Repare Therapeutics, Saint-Laurent, QC, Canada.
  • 2. Repare Therapeutics, Cambridge, MA, USA.
  • 3. Repare Therapeutics, Saint-Laurent, QC, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.
  • 4. Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
  • 5. Repare Therapeutics, Saint-Laurent, QC, Canada. Electronic address: [email protected].
  • 6. Repare Therapeutics, Saint-Laurent, QC, Canada. Electronic address: [email protected].
PMID: 42726641 DOI: 10.1016/j.celrep.2026.117961
Abstract

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.

Keywords
CP: cancer; CP: genomics; CRISPR screening; cancer driver mutations; cancer therapeutics; drug development; functional genomics; gene dependency; genetic vulnerabilities; genome-wide knockout; oncogene addiction; personalized medicine; precision oncology; synthetic lethality; target discovery; targeted oncology; tumor suppressor genes.
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