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Drug mechanism-of-action discovery through the integration of pharmacological and CRISPR screens.
Molecular Systems Biology ( IF 8.5 ) Pub Date : 2020-07-06 , DOI: 10.15252/msb.20199405
Emanuel Gonçalves 1 , Aldo Segura-Cabrera 2 , Clare Pacini 1 , Gabriele Picco 1 , Fiona M Behan 1 , Patricia Jaaks 1 , Elizabeth A Coker 1 , Donny van der Meer 1 , Andrew Barthorpe 1 , Howard Lightfoot 1 , Tatiana Mironenko 1 , Alexandra Beck 1 , Laura Richardson 1 , Wanjuan Yang 1 , Ermira Lleshi 1 , James Hall 1 , Charlotte Tolley 1 , Caitlin Hall 1 , Iman Mali 1 , Frances Thomas 1 , James Morris 1 , Andrew R Leach 2 , James T Lynch 3 , Ben Sidders 3 , Claire Crafter 3 , Francesco Iorio 1, 4 , Stephen Fawell 5 , Mathew J Garnett 1
Affiliation  

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.

中文翻译:


通过药理学和 CRISPR 筛选的整合发现药物作用机制。



药物开发过程中成功率低的部分原因是难以定义药物作用机制和治疗活性的分子标记。在这里,我们将 397 种独特抗癌药物的 199,219 项药物敏感性测量与 484 个细胞系中的全基因组 CRISPR 功能丧失筛选相结合,系统地研究细胞药物作用机制。我们观察到药物敏感性特征与药物名义靶标敲除之间存在丰富的正相关性,并且通过利用蛋白质-蛋白质网络,我们确定了支撑药物敏感性的途径。这揭示了乳腺癌细胞系中线粒体 E3 泛素-蛋白连接酶MARCH 5依赖性和对 MCL 1 抑制剂的敏感性之间存在未被认识到的正相关性。我们还评估了药物的靶向和脱靶活性,从而了解特异性、效力和毒性。将药物和基因依赖性与基因组数据集联系起来,揭示了分子网络在受到干扰时介导癌细胞适应性丧失的背景,从而为药物开发的生物标志物提供了独立和正交的证据。这项研究说明了如何将细胞系药物敏感性与 CRISPR 功能丧失筛选相结合,阐明作用机制以推进药物开发。
更新日期:2020-08-01
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