TY - JOUR T1 - Drug mechanism-of-action discovery through the integration of pharmacological and CRISPR screens JF - bioRxiv DO - 10.1101/2020.01.14.905729 SP - 2020.01.14.905729 AU - Emanuel Gonçalves AU - Aldo Segura-Cabrera AU - Clare Pacini AU - Gabriele Picco AU - Fiona M. Behan AU - Patricia Jaaks AU - Elizabeth A. Coker AU - Donny van der Meer AU - Andrew Barthorpe AU - Howard Lightfoot AU - GDSC Screening Team AU - Andrew R. Leach AU - James T. Lynch AU - Ben Sidders AU - Claire Crafter AU - Francesco Iorio AU - Stephen Fawell AU - Mathew J. Garnett Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/01/14/2020.01.14.905729.abstract N2 - Low success rates during drug development are due in part to the difficulty of defining drug mechanism-of-action and molecular markers of therapeutic activity. Here, we integrated 199,219 drug sensitivity measurements for 397 unique anti-cancer drugs and genome-wide CRISPR loss-of-function screens in 484 cell lines to systematically investigate in cellular drug mechanism-of-action. We observed an enrichment for positive associations between drug sensitivity and knockout of their nominal targets, and by leveraging protein-protein networks we identified pathways that mediate drug response. This revealed an unappreciated role of mitochondrial E3 ubiquitin-protein ligase MARCH5 in sensitivity to MCL1 inhibitors. We also estimated drug on-target and off-target activity, informing on specificity, potency and toxicity. Linking drug and gene dependency together with genomic datasets uncovered contexts in which molecular networks when perturbed mediate cancer cell loss-of-fitness, and thereby provide independent and orthogonal evidence of biomarkers for drug development. This study illustrates how integrating cell line drug sensitivity with CRISPR loss-of-function screens can elucidate mechanism-of-action to advance drug development. ER -