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

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, GDSC Screening Team, Andrew R. Leach, James T. Lynch, Ben Sidders, Claire Crafter, Francesco Iorio, Stephen Fawell, Mathew J. Garnett
doi: https://doi.org/10.1101/2020.01.14.905729
Emanuel Gonçalves
1Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK
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Aldo Segura-Cabrera
2European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, UK
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Clare Pacini
1Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK
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Gabriele Picco
1Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK
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Fiona M. Behan
1Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK
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Patricia Jaaks
1Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK
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Elizabeth A. Coker
1Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK
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Donny van der Meer
1Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK
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Andrew Barthorpe
1Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK
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Howard Lightfoot
1Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK
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1Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK
Andrew R. Leach
2European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, UK
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James T. Lynch
3Research and Early Development, Oncology R&D, AstraZeneca, Cambridge, UK
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Ben Sidders
3Research and Early Development, Oncology R&D, AstraZeneca, Cambridge, UK
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Claire Crafter
3Research and Early Development, Oncology R&D, AstraZeneca, Cambridge, UK
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Francesco Iorio
1Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK
5Human Technopole, Via Cristina Belgioioso, 20157 Milano, Italy
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Stephen Fawell
4Research and Early Development, Oncology R&D, AstraZeneca, Waltham, MA 02451, USA
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Mathew J. Garnett
1Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK
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  • For correspondence: mg12@sanger.ac.uk
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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 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.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted January 14, 2020.
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Drug mechanism-of-action discovery through the integration of pharmacological and CRISPR screens
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, GDSC Screening Team, Andrew R. Leach, James T. Lynch, Ben Sidders, Claire Crafter, Francesco Iorio, Stephen Fawell, Mathew J. Garnett
bioRxiv 2020.01.14.905729; doi: https://doi.org/10.1101/2020.01.14.905729
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Drug mechanism-of-action discovery through the integration of pharmacological and CRISPR screens
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, GDSC Screening Team, Andrew R. Leach, James T. Lynch, Ben Sidders, Claire Crafter, Francesco Iorio, Stephen Fawell, Mathew J. Garnett
bioRxiv 2020.01.14.905729; doi: https://doi.org/10.1101/2020.01.14.905729

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