A Chemical-Genetic Interaction Matrix Reveals Drug Mechanism and Genetic Architecture
Year: 2026
Type: preprint
Abstract: To probe drug mechanism of action (MOA) and interrogate the genetic architecture of human cells, we carried out isogenic genome-wide CRISPR/Cas9 knockout screens against 310 diverse drugs, bioactive compounds, and stress conditions. Stringent statistical correction for gene knockout fitness defects yielded a large-scale matrix of >12,000 high confidence chemical-genetic interactions (CGIs). This dataset revealed many previously unappreciated off-target effects for well-characterized compounds and novel MOAs for uncharacterized compounds. The CGI matrix uncovered dense genetic modules that yielded new biological insights into phospholipidosis, mitotic regulation, metabolism, the DNA damage response, and mTOR signaling. The dataset allowed identification of multi-drug sensitization and resistance mechanisms, inference of gene function, elaboration of cross-process connectivity, evaluation of the cell type specificity of CGIs, prediction of chemical synergism, and extensive annotation of understudied genes. This resource provides a map of the genetic landscape in human cells and a framework to help guide drug discovery.
Authors: Jasmin Coulombe-Huntington, Thierry Bertomeu, Caroline Huard, Andrew Chatr-aryamontri, Daniel J. St-Cyr, María Sánchez-Osuna, David Papadopoli, Karine Normandin, Mohammadjavad Paydar, Shannon McLaughlan, Corinne St-Denis, Li Zhang, Henry Say, Roger Palou, Chris Stark, Bobby-Joe Breitkreutz, Almer M. van der Sloot, Sandhya Manohar, Hugo Lavoie, Katherine L. B. Borden, Brian Raught, Damien D’Amours, Frank Sicheri, Alain Verreault, Sylvie Mader, Sylvain Meloche, Marc Therrien, Pierre Thibault, Brian Wilhelm, Peter B. Dirks, John D. Aitchison, Elizabeth Patton, Randall W. King, Philippe P. Roux, Guy Sauvageau, Trang Hoang, Anne Marinier, Lea Harrington, Benjamin Kwok, Vincent Archambault, Ivan Topisirovic, Mike Tyers
Institutions: Institute for Research in Immunology and Cancer, McGill University, Université de Montréal, Hospital for Sick Children, Mila - Quebec Artificial Intelligence Institute, University of Zurich, Northwestern University, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, University Health Network, University of Toronto, Princess Margaret Cancer Centre, University of Ottawa, Ottawa Institute of Systems Biology, Mount Sinai Hospital, Lunenfeld-Tanenbaum Research Institute, University of Washington, Seattle Children's Research Institute, Institute of Genetics and Cancer, MRC Human Genetics Unit, University of Edinburgh, Harvard University, University of Nebraska Medical Center
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funders: American Association for Cancer Research, W. M. Keck Foundation, Leukemia and Lymphoma Society, McGill University, Genome Canada, Government of Ontario, Government of Canada, Canada Foundation for Innovation, Terry Fox Foundation, Fondation pour la Recherche Médicale, Institut de Valorisation des Données, National Institutes of Health, Stand Up To Cancer, Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada, Medical Research Council, National Institute of General Medical Sciences
Awards: Regulation of chromosome architecture by SMC complexes in health and disease, G1528804057, G15564345, G1736451799, G2166824534, G2944979169, Architecture and chemical modulation of genetic networks, G3343289528, G3749782252, G4619069936, Molecular dissection of mitotic kinase functions using chemogenomics, G4777011349, G542072300, G5501108896, G6341843477, Targeting developmental cell states in melanoma, G7608025622, G8996608266, BioGRID: An open resource for biological interactions and network analysis, Mechanistic Analysis of the Ubiquitin-Proteasome System
OpenAlex ID: W7126037217