Drug mechanism-of-action discovery through the integration of pharmacological and CRISPR screens.
Mol Syst Biol
; 16(7): e9405, 2020 07.
Article
em En
| MEDLINE
| ID: mdl-32627965
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.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Ensaios de Seleção de Medicamentos Antitumorais
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Redes Reguladoras de Genes
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Aptidão Genética
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Mapas de Interação de Proteínas
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Sistemas CRISPR-Cas
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Desenvolvimento de Medicamentos
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Antineoplásicos
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article