Open AccessDrug mechanism‐of‐action discovery through the integration of pharmacological and CRISPR screens
Author(s) -
Gonçalves Emanuel,
SeguraCabrera Aldo,
Pacini Clare,
Picco Gabriele,
Behan Fiona M,
Jaaks Patricia,
Coker Elizabeth A,
Meer Donny,
Barthorpe Andrew,
Lightfoot Howard,
Mironenko Tatiana,
Beck Alexandra,
Richardson Laura,
Yang Wanjuan,
Lleshi Ermira,
Hall James,
Tolley Charlotte,
Hall Caitlin,
Mali Iman,
Thomas Frances,
Morris James,
Leach Andrew R,
Lynch James T,
Sidders Ben,
Crafter Claire,
Iorio Francesco,
Fawell Stephen,
Garnett Mathew J
Publication year - 2020
Publication title -
molecular systems biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 8.523
H-Index - 148
ISSN - 1744-4292
DOI - 10.15252/msb.20199405
Subject(s) - biology , drug discovery , crispr , drug , computational biology , drug action , drug development , mechanism (biology) , mechanism of action , loss function , function (biology) , genetics , bioinformatics , pharmacology , gene , phenotype , in vitro , philosophy , epistemology
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 with genome‐wide CRISPR loss‐of‐function screens in 484 cell lines to systematically investigate cellular drug mechanism‐of‐action. We observed an enrichment for positive associations between the profile of drug sensitivity and knockout of a drug's nominal target, and by leveraging protein–protein networks, we identified pathways underpinning drug sensitivity. This revealed an unappreciated positive association between mitochondrial E3 ubiquitin–protein ligase MARCH 5 dependency and sensitivity to MCL 1 inhibitors in breast cancer cell lines. We also estimated drug on‐target and off‐target activity, informing on specificity, potency and toxicity. Linking drug and gene dependency together with genomic data sets 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.