Genome-wide CRISPR-Cas9 screens identify mechanisms of BET bromodomain inhibitor sensitivity

Summary: BET bromodomain inhibitors hold promise as therapeutic agents in diverse indications, but their clinical progression has been challenging and none have received regulatory approval. Early clinical trials in cancer have shown heterogeneous clinical responses, development of resistance, and a...

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Autores principales:	David Estoppey, Gabi Schutzius, Christian Kolter, Adrian Salathe, Tiffany Wunderlin, Amandine Meyer, Florian Nigsch, Tewis Bouwmeester, Dominic Hoepfner, Susan Kirkland
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	Molecular biology Cell biology Chemogenomics Science Q
Acceso en línea:	https://doaj.org/article/bfd4227e84094d04b3e9d533cdc982de
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spelling	oai:doaj.org-article:bfd4227e84094d04b3e9d533cdc982de2021-11-20T05:09:56ZGenome-wide CRISPR-Cas9 screens identify mechanisms of BET bromodomain inhibitor sensitivity2589-004210.1016/j.isci.2021.103323https://doaj.org/article/bfd4227e84094d04b3e9d533cdc982de2021-11-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S258900422101292Xhttps://doaj.org/toc/2589-0042Summary: BET bromodomain inhibitors hold promise as therapeutic agents in diverse indications, but their clinical progression has been challenging and none have received regulatory approval. Early clinical trials in cancer have shown heterogeneous clinical responses, development of resistance, and adverse events. Increased understanding of their mechanism(s) of action and identification of biomarkers are needed to identify appropriate indication(s) and achieve efficacious dosing. Using genome-wide CRISPR-Cas9 screens at different concentrations, we report molecular mechanisms defining cellular responses to BET inhibitors, some of which appear specific to a single compound concentration. We identify multiple transcriptional regulators and mTOR pathway members as key determinants of JQ1 sensitivity and two Ca2+/Mn2+ transporters, ATP2C1 and TMEM165, as key determinants of JQ1 resistance. Our study reveals new molecular mediators of BET bromodomain inhibitor effects, suggests the involvement of manganese, and provides a rich resource for discovery of biomarkers and targets for combination therapies.David EstoppeyGabi SchutziusChristian KolterAdrian SalatheTiffany WunderlinAmandine MeyerFlorian NigschTewis BouwmeesterDominic HoepfnerSusan KirklandElsevierarticleMolecular biologyCell biologyChemogenomicsScienceQENiScience, Vol 24, Iss 11, Pp 103323- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Molecular biology Cell biology Chemogenomics Science Q
spellingShingle	Molecular biology Cell biology Chemogenomics Science Q David Estoppey Gabi Schutzius Christian Kolter Adrian Salathe Tiffany Wunderlin Amandine Meyer Florian Nigsch Tewis Bouwmeester Dominic Hoepfner Susan Kirkland Genome-wide CRISPR-Cas9 screens identify mechanisms of BET bromodomain inhibitor sensitivity
description	Summary: BET bromodomain inhibitors hold promise as therapeutic agents in diverse indications, but their clinical progression has been challenging and none have received regulatory approval. Early clinical trials in cancer have shown heterogeneous clinical responses, development of resistance, and adverse events. Increased understanding of their mechanism(s) of action and identification of biomarkers are needed to identify appropriate indication(s) and achieve efficacious dosing. Using genome-wide CRISPR-Cas9 screens at different concentrations, we report molecular mechanisms defining cellular responses to BET inhibitors, some of which appear specific to a single compound concentration. We identify multiple transcriptional regulators and mTOR pathway members as key determinants of JQ1 sensitivity and two Ca2+/Mn2+ transporters, ATP2C1 and TMEM165, as key determinants of JQ1 resistance. Our study reveals new molecular mediators of BET bromodomain inhibitor effects, suggests the involvement of manganese, and provides a rich resource for discovery of biomarkers and targets for combination therapies.
format	article
author	David Estoppey Gabi Schutzius Christian Kolter Adrian Salathe Tiffany Wunderlin Amandine Meyer Florian Nigsch Tewis Bouwmeester Dominic Hoepfner Susan Kirkland
author_facet	David Estoppey Gabi Schutzius Christian Kolter Adrian Salathe Tiffany Wunderlin Amandine Meyer Florian Nigsch Tewis Bouwmeester Dominic Hoepfner Susan Kirkland
author_sort	David Estoppey
title	Genome-wide CRISPR-Cas9 screens identify mechanisms of BET bromodomain inhibitor sensitivity
title_short	Genome-wide CRISPR-Cas9 screens identify mechanisms of BET bromodomain inhibitor sensitivity
title_full	Genome-wide CRISPR-Cas9 screens identify mechanisms of BET bromodomain inhibitor sensitivity
title_fullStr	Genome-wide CRISPR-Cas9 screens identify mechanisms of BET bromodomain inhibitor sensitivity
title_full_unstemmed	Genome-wide CRISPR-Cas9 screens identify mechanisms of BET bromodomain inhibitor sensitivity
title_sort	genome-wide crispr-cas9 screens identify mechanisms of bet bromodomain inhibitor sensitivity
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/bfd4227e84094d04b3e9d533cdc982de
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_version_	1718419564493012992

Genome-wide CRISPR-Cas9 screens identify mechanisms of BET bromodomain inhibitor sensitivity

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