Detection of phenotype-specific therapeutic vulnerabilities in breast cells using a CRISPR loss-of-function screen.
Mol Oncol
; 15(8): 2026-2045, 2021 08.
Article
en En
| MEDLINE
| ID: mdl-33759347
ABSTRACT
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.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Fenotipo
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Neoplasias de la Mama Triple Negativas
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Sistemas CRISPR-Cas
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Mutación con Pérdida de Función
Tipo de estudio:
Diagnostic_studies
Límite:
Female
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Humans
Idioma:
En
Año:
2021
Tipo del documento:
Article