CRISPR screens identify tumor‐promoting genes conferring melanoma cell plasticity and resistance

Autor: Arthur Gautron, Laura Bachelot, Marc Aubry, Delphine Leclerc, Anaïs M Quéméner, Sébastien Corre, Florian Rambow, Anaïs Paris, Nina Tardif, Héloïse M Leclair, Oskar Marin‐Bejar, Cédric Coulouarn, Jean‐Christophe Marine, Marie‐Dominique Galibert, David Gilot
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Zdroj: EMBO Molecular Medicine, Vol 13, Iss 5, Pp 1-22 (2021)
Druh dokumentu: article
ISSN: 20201346
1757-4676
1757-4684
DOI: 10.15252/emmm.202013466
Popis: Abstract Most genetic alterations that drive melanoma development and resistance to targeted therapy have been uncovered. In contrast, and despite their increasingly recognized contribution, little is known about the non‐genetic mechanisms that drive these processes. Here, we performed in vivo gain‐of‐function CRISPR screens and identified SMAD3, BIRC3, and SLC9A5 as key actors of BRAFi resistance. We show that their expression levels increase during acquisition of BRAFi resistance and remain high in persister cells and during relapse. The upregulation of the SMAD3 transcriptional activity (SMAD3‐signature) promotes a mesenchymal‐like phenotype and BRAFi resistance by acting as an upstream transcriptional regulator of potent BRAFi‐resistance genes such as EGFR and AXL. This SMAD3‐signature predicts resistance to both current melanoma therapies in different cohorts. Critically, chemical inhibition of SMAD3 may constitute amenable target for melanoma since it efficiently abrogates persister cells survival. Interestingly, decrease of SMAD3 activity can also be reached by inhibiting the Aryl hydrocarbon Receptor (AhR), another druggable transcription factor governing SMAD3 expression level. Our work highlights novel drug vulnerabilities that can be exploited to develop long‐lasting antimelanoma therapies.
Databáze: Directory of Open Access Journals
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