Drug mechanism-of-action discovery through the integration of pharmacological and CRISPR screens.

Abstract

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 MARCH5 dependency and sensitivity to MCL1 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.

• Authors: Emanuel Gonçalves, Aldo Segura-Cabrera, Clare Pacini, Gabriele Picco, Fiona M Behan, Patricia Jaaks, Elizabeth A Coker, Donny van der Meer, Andrew Barthorpe, Howard Lightfoot, Tatiana Mironenko, Alexandra Beck, Laura Richardson, Wanjuan Yang, Ermira Lleshi, James Hall, Charlotte Tolley, Caitlin Hall, Iman Mali, Frances Thomas, James Morris, Andrew R Leach, James T Lynch, Ben Sidders, Claire Crafter, Francesco Iorio, Stephen Fawell, Mathew J Garnett
• Journal: Molecular systems biology (Mol Syst Biol) Vol. 16 Issue 7 Pg. e9405 (07 2020) ISSN: 1744-4292 [Electronic] England
• PMID: 32627965 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 The Authors. Published under the terms of the CC BY 4.0 license.

Chemical References

• Antineoplastic Agents
• Biomarkers
• MCL1 protein, human
• Membrane Proteins
• Myeloid Cell Leukemia Sequence 1 Protein
• Pharmaceutical Preparations
• MARCHF5 protein, human
• Ubiquitin-Protein Ligases

Topics

• Antineoplastic Agents (pharmacology, toxicity)
• Biomarkers (metabolism)
• CRISPR-Cas Systems
• Cell Line, Tumor
• Drug Development (methods)
• Drug Screening Assays, Antitumor (methods)
• Gene Knockout Techniques
• Gene Regulatory Networks (drug effects, genetics)
• Genetic Fitness (drug effects, genetics)
• Genomics
• Humans
• Linear Models
• Membrane Proteins (genetics, metabolism)
• Myeloid Cell Leukemia Sequence 1 Protein (antagonists & inhibitors)
• Pharmaceutical Preparations (metabolism)
• Protein Interaction Maps (drug effects)
• Software
• Ubiquitin-Protein Ligases (genetics, metabolism)