biostudies-literatureHarle VHealth Research Charities IrelandOpenTargetsAstra ZenecaWellcome Trust284https://www.ebi.ac.uk/biostudies/studies/S-EPMC12445041biostudies-literatureUnknown26(1)<h4>Background</h4>Synthetic lethal interactions are attractive therapeutic candidates as they enable selective targeting of cancer cells in which somatic alterations have disrupted one member of a synthetic lethal gene pair while leaving normal tissues untouched, thus minimising off-target toxicity. Despite this potential, the number of well-established and validated synthetic lethal gene pairs is modest.<h4>Results</h4>We generate a dual-guide CRISPR/Cas9 Library and analyse 472 predicted synthetic lethal pairs in 27 cancer cell Lines from melanoma, pancreatic and lung cancer Lineages. We report a robust collection of 117 genetic interactions within and across cancer types and explore their candidacy as therapeutic targets. We show that SLC25A28 is an attractive target since its synthetiGenome biologyA compendium of synthetic lethal gene pairs defined by extensive combinatorial pan-cancer CRISPR screening.PMC12445041220540/Z/20/A20/FFP-P/8641 and 18/CRT/6214Olvera-Leon RKebabci NThompson NALi LMehta IOfford VRyan CJPeidli Svan de Haar JAdams DJAlexander DGoncalves EHarle VGokbag BDe Kegel BWilliams TIyer VFotopoulos LfalseA compendium of synthetic lethal gene pairs defined by extensive combinatorial pan-cancer CRISPR screening.<h4>Background</h4>Synthetic lethal interactions are attractive therapeutic candidates as they enable selective targeting of cancer cells in which somatic alterations have disrupted one member of a synthetic lethal gene pair while leaving normal tissues untouched, thus minimising off-target toxicity. Despite this potential, the number of well-established and validated synthetic lethal gene pairs is modest.<h4>Results</h4>We generate a dual-guide CRISPR/Cas9 Library and analyse 472 predicted synthetic lethal pairs in 27 cancer cell Lines from melanoma, pancreatic and lung cancer Lineages. We report a robust collection of 117 genetic interactions within and across cancer types and explore their candidacy as therapeutic targets. We show that SLC25A28 is an attractive target since its syntheti2025-01-01T00:00:00Z2025 Sep2026-06-03T15:40:13.295Z2026-04-29T03:12:40.215ZS-EPMC124450414096837210.1186/s13059-025-03737-w