دورية أكاديمية
Detection of phenotype‐specific therapeutic vulnerabilities in breast cells using a CRISPR loss‐of‐function screen
| العنوان: | Detection of phenotype‐specific therapeutic vulnerabilities in breast cells using a CRISPR loss‐of‐function screen |
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| المؤلفون: | Anna Barkovskaya, Craig M. Goodwin, Kotryna Seip, Bylgja Hilmarsdottir, Solveig Pettersen, Clint Stalnecker, Olav Engebraaten, Eirikur Briem, Channing J. Der, Siver A. Moestue, Thorarinn Gudjonsson, Gunhild M. Mælandsmo, Lina Prasmickaite |
| المصدر: | Molecular Oncology, Vol 15, Iss 8, Pp 2026-2045 (2021) |
| بيانات النشر: | Wiley, 2021. |
| سنة النشر: | 2021 |
| المجموعة: | LCC:Neoplasms. Tumors. Oncology. Including cancer and carcinogens |
| مصطلحات موضوعية: | actionable targets, CRISPR knockout screen, epithelial–mesenchymal transition, phenotype plasticity, therapeutic vulnerabilities, triple‐negative breast cancer, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282 |
| الوصف: | Cellular 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 G2‐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), G2‐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. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 1878-0261 1574-7891 |
| Relation: | https://doaj.org/toc/1574-7891; https://doaj.org/toc/1878-0261 |
| DOI: | 10.1002/1878-0261.12951 |
| URL الوصول: | https://doaj.org/article/0cf47b80942b4dccb4f54632467c29f1 |
| رقم الأكسشن: | edsdoj.0cf47b80942b4dccb4f54632467c29f1 |
| قاعدة البيانات: | Directory of Open Access Journals |
Full Text Finder | تدمد: | 18780261 15747891 |
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| DOI: | 10.1002/1878-0261.12951 |