期刊
EMBO MOLECULAR MEDICINE
卷 13, 期 5, 页码 -出版社
WILEY
DOI: 10.15252/emmm.202013466
关键词
Aryl hydrocarbon Receptor; CRISPR‐ SAM; melanoma; SMAD3; targeted therapy resistance
资金
- Human and Environmental Genomics platform
- Fondation ARC pour la Recherche (ARC)
- Ligue Nationale Contre le Cancer (LNCC)
- Departements du Grand-Ouest
- Region Bretagne
- University of Rennes 1
- CNRS
- SFR Biosit, Association Vaincre le Cancer
- Ligue Nationale Contre le Cancer (LNCC) Grand Ouest fellowship
- Fondation ARC pour la Recherche
- LNCC
- French Ministry of Research
- Institut National contre le Cancer (INCa)
Genetic drivers of melanoma development and therapy resistance have been identified, but non-genetic mechanisms are less understood. Through in vivo CRISPR screens, SMAD3, BIRC3, and SLC9A5 were found to play key roles in BRAFi resistance. Upregulation of SMAD3 was linked to resistance prediction and chemical inhibition of SMAD3 showed promise in targeting persister cells associated with melanoma.
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.
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