Identifying chemogenetic interactions from CRISPR knockout screens with drugZ

Abstract 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 largely 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. Additionally, drugZ confirms KEAP1 loss as a resistance factor for ERK inhibitors in oncogenic KRAS backgrounds and identifies additional cell-specific mechanisms of drug resistance. The software is available at github.com/hart-lab/drugz.