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dc.contributor.authorBarkovskaya, Anna
dc.contributor.authorGoodwin, Craig
dc.contributor.authorSeip, Kotryna
dc.contributor.authorHilmarsdòttir, Bylgja
dc.contributor.authorPettersen, Solveig
dc.contributor.authorStalnecker, Clint
dc.contributor.authorEngebraaten, Olav
dc.contributor.authorBriem, Eirikur
dc.contributor.authorDer, Channing J
dc.contributor.authorMoestue, Siver Andreas
dc.contributor.authorGuðjónsson, Þórarinn
dc.contributor.authorMælandsmo, Gunhild Mari
dc.contributor.authorPrasmickaite, Lina
dc.date.accessioned2021-09-28T08:31:34Z
dc.date.available2021-09-28T08:31:34Z
dc.date.issued2021-03-24
dc.description.abstractCellular phenotype plasticity between the epithelial and mesenchymal states has been linked to metastasis and heterogeneous responses to cancer therapy, and remains a challenge for the treatment of triple-negative breast cancer (TNBC). Here, we used isogenic human breast epithelial cell lines, D492 and D492M, representing the epithelial and mesenchymal phenotypes, respectively. We employed a CRISPR-Cas9 loss-of-function screen targeting a 2240-gene ‘druggable genome’ to identify phenotype-specific vulnerabilities. Cells with the epithelial phenotype were more vulnerable to the loss of genes related to EGFR-RAS-MAPK signaling, while the mesenchymal-like cells had increased sensitivity to knockout of G<sub>2</sub>-M cell cycle regulators. Furthermore, we discovered knockouts that sensitize to the mTOR inhibitor everolimus and the chemotherapeutic drug fluorouracil in a phenotype-specific manner. Specifically, loss of EGFR and fatty acid synthase (FASN) increased the effectiveness of the drugs in the epithelial and mesenchymal phenotypes, respectively. These phenotype-associated genetic vulnerabilities were confirmed using targeted inhibitors of EGFR (gefitinib), G<sub>2</sub>-M transition (STLC), and FASN (Fasnall). In conclusion, a CRISPR-Cas9 loss-of-function screen enables the identification of phenotype-specific genetic vulnerabilities that can pinpoint actionable targets and promising therapeutic combinations.en_US
dc.identifier.citationBarkovskaya, Goodwin, Seip, Hilmarsdòttir, Pettersen, Stalnecker, Engebraaten, Briem, Der, Moestue, Guðjónsson, Mælandsmo, Prasmickaite. Detection of phenotype-specific therapeutic vulnerabilities in breast cells using a CRISPR loss-of-function screen. Molecular Oncology. 2021en_US
dc.identifier.cristinIDFRIDAID 1896057
dc.identifier.doi10.1002/1878-0261.12951
dc.identifier.issn1574-7891
dc.identifier.issn1878-0261
dc.identifier.urihttps://hdl.handle.net/10037/22680
dc.language.isoengen_US
dc.publisherWiley Open Accessen_US
dc.relation.journalMolecular Oncology
dc.relation.projectIDNorges forskningsråd: 239940en_US
dc.relation.projectIDinfo:eu-repo/grantAgreement/RCN/FRIMEDBIO/239940/Norway/Cancer metabolism: From basic biochemistry to clinical opportunities//en_US
dc.rights.accessRightsopenAccessen_US
dc.rights.holderCopyright 2021 The Author(s)en_US
dc.subjectVDP::Medical disciplines: 700en_US
dc.subjectVDP::Medisinske Fag: 700en_US
dc.titleDetection of phenotype-specific therapeutic vulnerabilities in breast cells using a CRISPR loss-of-function screenen_US
dc.type.versionpublishedVersionen_US
dc.typeJournal articleen_US
dc.typeTidsskriftartikkelen_US
dc.typePeer revieweden_US


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