Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
UTHealth Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Genome Med. 2019 Aug 22;11(1):52. doi: 10.1186/s13073-019-0665-3.
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.
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.
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 .
化学遗传学分析能够鉴定出增强或抑制化合物活性的基因突变。这些知识为药物作用机制、遗传脆弱性和耐药机制提供了深入的了解，所有这些都可能有助于对患者群体进行分层，并提高药物疗效。基于 CRISPR 的筛选能够在人类细胞中直接灵敏地检测药物-基因相互作用，但直到最近，它主要用于筛选耐药机制。
我们提出了 drugZ，这是一种从 CRISPR 筛选中识别协同和抑制性化学遗传学相互作用的算法。DrugZ 鉴定了 PARP 抑制剂与 DNA 损伤修复途径中已知和新的成员之间的合成致死相互作用，证实 KEAP1 缺失是致癌性 KRAS 背景下 ERK 抑制剂的耐药因素，并定义了替莫唑胺活性的遗传背景。
DrugZ 是一个用于分析全基因组药物修饰筛选的开源 Python 软件。该软件能够准确识别增强或抑制药物活性的遗传扰动。有趣的是，对新的和以前发表的数据的分析表明，在药物修饰筛选中，肿瘤抑制基因是无药物特异性的耐药基因。该软件可在 github.com/hart-lab/drugz 获得。
