期刊
GENOME MEDICINE
卷 11, 期 1, 页码 -出版社
BMC
DOI: 10.1186/s13073-019-0665-3
关键词
CRISPR screens; Chemogenetic interactions; Drug resistance; Synthetic lethality
资金
- MD Anderson Cancer Center Support Grant [P30 CA016672]
- Cancer Prevention Research Institute of Texas (CPRIT) [RR160032]
- NIGMS [R35GM130119]
- CIHR [361837, 342551, 365646, FDN143343]
- Canadian Cancer Society [70389]
- Krembil Foundation
Background: Chemogenetic profiling enables the identification of gene mutations that enhance or suppress the activity of chemical compounds. This knowledge provides insights into drug mechanism of action, genetic vulnerabilities, and resistance mechanisms, all of which may help stratify patient populations and improve drug efficacy. CRISPR-based screening enables sensitive detection of drug-gene interactions directly in human cells, but until recently has primarily been used to screen only for resistance mechanisms. Results: We present drugZ, an algorithm for identifying both synergistic and suppressor chemogenetic interactions from CRISPR screens. DrugZ identifies synthetic lethal interactions between PARP inhibitors and both known and novel members of the DNA damage repair pathway, confirms KEAP1 loss as a resistance factor for ERK inhibitors in oncogenic KRAS backgrounds, and defines the genetic context for temozolomide activity. Conclusions: DrugZ is an open-source Python software for the analysis of genome-scale drug modifier screens. The software accurately identifies genetic perturbations that enhance or suppress drug activity. Interestingly, analysis of new and previously published data reveals tumor suppressor genes are drug-agnostic resistance genes in drug modifier screens. The software is available at github.com/hart-lab/drugz.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据