期刊
MOLECULAR SYSTEMS BIOLOGY
卷 16, 期 7, 页码 -出版社
WILEY
DOI: 10.15252/msb.20199405
关键词
CRISPR-Cas9; drug mechanism-of-action; protein networks
资金
- Wellcome [206194]
- AstraZeneca
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-wideCRISPRloss-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 ligaseMARCH5dependency and sensitivity toMCL1 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 withCRISPRloss-of-function screens can elucidate mechanism-of-action to advance drug development.
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