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Here, we used isogenic human breast epithelial cell lines, D492 and D492M, representing the epithelial and mesenchymal phenotypes, respectively. We employed a CRISPR\u2010Cas9 loss\u2010of\u2010function screen targeting a 2240\u2010gene \u2018druggable genome\u2019 to identify phenotype\u2010specific vulnerabilities. Cells with the epithelial phenotype were more vulnerable to the loss of genes related to EGFR\u2010RAS\u2010MAPK signaling, while the mesenchymal\u2010like cells had increased sensitivity to knockout of G<jats:sub>2<\/jats:sub>\u2010M cell cycle regulators. Furthermore, we discovered knockouts that sensitize to the mTOR inhibitor everolimus and the chemotherapeutic drug fluorouracil in a phenotype\u2010specific 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\u2010associated genetic vulnerabilities were confirmed using targeted inhibitors of EGFR (gefitinib), G<jats:sub>2<\/jats:sub>\u2010M transition (STLC), and FASN (Fasnall). In conclusion, a CRISPR\u2010Cas9 loss\u2010of\u2010function screen enables the identification of phenotype\u2010specific genetic vulnerabilities that can pinpoint actionable targets and promising therapeutic combinations.<\/jats:p>","DOI":"10.1002\/1878-0261.12951","type":"journal-article","created":{"date-parts":[[2021,3,24]],"date-time":"2021-03-24T07:46:43Z","timestamp":1616572003000},"page":"2026-2045","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Detection of phenotype\u2010specific therapeutic vulnerabilities in breast cells using a CRISPR loss\u2010of\u2010function screen"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9465-9444","authenticated-orcid":false,"given":"Anna","family":"Barkovskaya","sequence":"first","affiliation":[{"name":"Department of Tumor Biology Institute for Cancer Research Oslo University Hospital The Norwegian Radium Hospital Oslo 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