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A targeted genetic modifier screen in Drosophila uncovers vulnerabilities in a genetically complex model of colon cancer

Received on 16 January 2023; accepted on 21 February 2023Kinases are key regulators of cellular signal transduction pathways. Many diseases, including cancer, are associated with global alterations in protein phosphorylation networks. As a result, kinases are frequent targets of drug discovery effor...

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Autores principales: Datta, Ishwaree, Vassel, Tajah, Linkous, Benjamin, Odum, Tyler, Drew, Christian, Taylor, Andrew, Bangi, Erdem
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10151408/
https://www.ncbi.nlm.nih.gov/pubmed/36880303
http://dx.doi.org/10.1093/g3journal/jkad053
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author Datta, Ishwaree
Vassel, Tajah
Linkous, Benjamin
Odum, Tyler
Drew, Christian
Taylor, Andrew
Bangi, Erdem
author_facet Datta, Ishwaree
Vassel, Tajah
Linkous, Benjamin
Odum, Tyler
Drew, Christian
Taylor, Andrew
Bangi, Erdem
author_sort Datta, Ishwaree
collection PubMed
description Received on 16 January 2023; accepted on 21 February 2023Kinases are key regulators of cellular signal transduction pathways. Many diseases, including cancer, are associated with global alterations in protein phosphorylation networks. As a result, kinases are frequent targets of drug discovery efforts. However, target identification and assessment, a critical step in targeted drug discovery that involves identifying essential genetic mediators of disease phenotypes, can be challenging in complex, heterogeneous diseases like cancer, where multiple concurrent genomic alterations are common. Drosophila is a particularly useful genetic model system to identify novel regulators of biological processes through unbiased genetic screens. Here, we report 2 classic genetic modifier screens focusing on the Drosophila kinome to identify kinase regulators in 2 different backgrounds: KRAS TP53 PTEN APC, a multigenic cancer model that targets 4 genes recurrently mutated in human colon tumors and KRAS alone, a simpler model that targets one of the most frequently altered pathways in cancer. These screens identified hits unique to each model and one shared by both, emphasizing the importance of capturing the genetic complexity of human tumor genome landscapes in experimental models. Our follow-up analysis of 2 hits from the KRAS-only screen suggests that classical genetic modifier screens in heterozygous mutant backgrounds that result in a modest, nonlethal reduction in candidate gene activity in the context of a whole animal—a key goal of systemic drug treatment—may be a particularly useful approach to identify the most rate-limiting genetic vulnerabilities in disease models as ideal candidate drug targets.
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spelling pubmed-101514082023-05-03 A targeted genetic modifier screen in Drosophila uncovers vulnerabilities in a genetically complex model of colon cancer Datta, Ishwaree Vassel, Tajah Linkous, Benjamin Odum, Tyler Drew, Christian Taylor, Andrew Bangi, Erdem G3 (Bethesda) Mutant Screen Report Received on 16 January 2023; accepted on 21 February 2023Kinases are key regulators of cellular signal transduction pathways. Many diseases, including cancer, are associated with global alterations in protein phosphorylation networks. As a result, kinases are frequent targets of drug discovery efforts. However, target identification and assessment, a critical step in targeted drug discovery that involves identifying essential genetic mediators of disease phenotypes, can be challenging in complex, heterogeneous diseases like cancer, where multiple concurrent genomic alterations are common. Drosophila is a particularly useful genetic model system to identify novel regulators of biological processes through unbiased genetic screens. Here, we report 2 classic genetic modifier screens focusing on the Drosophila kinome to identify kinase regulators in 2 different backgrounds: KRAS TP53 PTEN APC, a multigenic cancer model that targets 4 genes recurrently mutated in human colon tumors and KRAS alone, a simpler model that targets one of the most frequently altered pathways in cancer. These screens identified hits unique to each model and one shared by both, emphasizing the importance of capturing the genetic complexity of human tumor genome landscapes in experimental models. Our follow-up analysis of 2 hits from the KRAS-only screen suggests that classical genetic modifier screens in heterozygous mutant backgrounds that result in a modest, nonlethal reduction in candidate gene activity in the context of a whole animal—a key goal of systemic drug treatment—may be a particularly useful approach to identify the most rate-limiting genetic vulnerabilities in disease models as ideal candidate drug targets. Oxford University Press 2023-03-06 /pmc/articles/PMC10151408/ /pubmed/36880303 http://dx.doi.org/10.1093/g3journal/jkad053 Text en © The Author(s) 2023. Published by Oxford University Press on behalf of The Genetics Society of America. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Mutant Screen Report
Datta, Ishwaree
Vassel, Tajah
Linkous, Benjamin
Odum, Tyler
Drew, Christian
Taylor, Andrew
Bangi, Erdem
A targeted genetic modifier screen in Drosophila uncovers vulnerabilities in a genetically complex model of colon cancer
title A targeted genetic modifier screen in Drosophila uncovers vulnerabilities in a genetically complex model of colon cancer
title_full A targeted genetic modifier screen in Drosophila uncovers vulnerabilities in a genetically complex model of colon cancer
title_fullStr A targeted genetic modifier screen in Drosophila uncovers vulnerabilities in a genetically complex model of colon cancer
title_full_unstemmed A targeted genetic modifier screen in Drosophila uncovers vulnerabilities in a genetically complex model of colon cancer
title_short A targeted genetic modifier screen in Drosophila uncovers vulnerabilities in a genetically complex model of colon cancer
title_sort targeted genetic modifier screen in drosophila uncovers vulnerabilities in a genetically complex model of colon cancer
topic Mutant Screen Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10151408/
https://www.ncbi.nlm.nih.gov/pubmed/36880303
http://dx.doi.org/10.1093/g3journal/jkad053
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