Identifying chemogenetic interactions from CRISPR screens with drugZ
Abstract 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 pati...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2019-08-01
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| Series: | Genome Medicine |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13073-019-0665-3 |
| _version_ | 1818326316695420928 |
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| author | Medina Colic Gang Wang Michal Zimmermann Keith Mascall Megan McLaughlin Lori Bertolet W. Frank Lenoir Jason Moffat Stephane Angers Daniel Durocher Traver Hart |
| author_facet | Medina Colic Gang Wang Michal Zimmermann Keith Mascall Megan McLaughlin Lori Bertolet W. Frank Lenoir Jason Moffat Stephane Angers Daniel Durocher Traver Hart |
| author_sort | Medina Colic |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-12-13T11:58:27Z |
| format | Article |
| id | doaj.art-0660691297e4473f951c2f4ee9ed5f00 |
| institution | Directory Open Access Journal |
| issn | 1756-994X |
| language | English |
| last_indexed | 2024-12-13T11:58:27Z |
| publishDate | 2019-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Genome Medicine |
| spelling | doaj.art-0660691297e4473f951c2f4ee9ed5f002022-12-21T23:47:09ZengBMCGenome Medicine1756-994X2019-08-0111111210.1186/s13073-019-0665-3Identifying chemogenetic interactions from CRISPR screens with drugZMedina Colic0Gang Wang1Michal Zimmermann2Keith Mascall3Megan McLaughlin4Lori Bertolet5W. Frank Lenoir6Jason Moffat7Stephane Angers8Daniel Durocher9Traver Hart10Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer CenterDepartment of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer CenterLunenfeld-Tanenbaum Research Institute, Mount Sinai HospitalDepartment of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of TorontoDepartment of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer CenterDepartment of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer CenterDepartment of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer CenterDonnelly Centre, University of TorontoDepartment of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of TorontoLunenfeld-Tanenbaum Research Institute, Mount Sinai HospitalDepartment of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer CenterAbstract 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.http://link.springer.com/article/10.1186/s13073-019-0665-3CRISPR screensChemogenetic interactionsDrug resistanceSynthetic lethality |
| spellingShingle | Medina Colic Gang Wang Michal Zimmermann Keith Mascall Megan McLaughlin Lori Bertolet W. Frank Lenoir Jason Moffat Stephane Angers Daniel Durocher Traver Hart Identifying chemogenetic interactions from CRISPR screens with drugZ Genome Medicine CRISPR screens Chemogenetic interactions Drug resistance Synthetic lethality |
| title | Identifying chemogenetic interactions from CRISPR screens with drugZ |
| title_full | Identifying chemogenetic interactions from CRISPR screens with drugZ |
| title_fullStr | Identifying chemogenetic interactions from CRISPR screens with drugZ |
| title_full_unstemmed | Identifying chemogenetic interactions from CRISPR screens with drugZ |
| title_short | Identifying chemogenetic interactions from CRISPR screens with drugZ |
| title_sort | identifying chemogenetic interactions from crispr screens with drugz |
| topic | CRISPR screens Chemogenetic interactions Drug resistance Synthetic lethality |
| url | http://link.springer.com/article/10.1186/s13073-019-0665-3 |
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