Nrf2 as a Therapeutic Target in the Resistance to Targeted Therapies in Melanoma.
A375 cell line
BRAFi/MEKi
D4M cell line
DUB3
Nrf2
YAP
dabrafenib
melanoma
targeted therapy resistance
trametinib
Journal
Antioxidants (Basel, Switzerland)
ISSN: 2076-3921
Titre abrégé: Antioxidants (Basel)
Pays: Switzerland
ID NLM: 101668981
Informations de publication
Date de publication:
20 Jun 2023
20 Jun 2023
Historique:
received:
25
05
2023
revised:
16
06
2023
accepted:
16
06
2023
medline:
28
6
2023
pubmed:
28
6
2023
entrez:
28
6
2023
Statut:
epublish
Résumé
The use of specific inhibitors towards mutant BRAF (BRAFi) and MEK (MEKi) in BRAF-mutated patients has significantly improved progression-free and overall survival of metastatic melanoma patients. Nevertheless, half of the patients still develop resistance within the first year of therapy. Therefore, understanding the mechanisms of BRAFi/MEKi-acquired resistance has become a priority for researchers. Among others, oxidative stress-related mechanisms have emerged as a major force. The aim of this study was to evaluate the contribution of Nrf2, the master regulator of the cytoprotective and antioxidant response, in the BRAFi/MEKi acquired resistance of melanoma. Moreover, we investigated the mechanisms of its activity regulation and the possible cooperation with the oncogene YAP, which is also involved in chemoresistance. Taking advantage of established in vitro melanoma models resistant to BRAFi, MEKi, or dual resistance to BRAFi/MEKi, we demonstrated that Nrf2 was upregulated in melanoma cells resistant to targeted therapy at the post-translational level and that the deubiquitinase DUB3 participated in the control of the Nrf2 protein stability. Furthermore, we found that Nrf2 controlled the expression of YAP. Importantly, the inhibition of Nrf2, directly or through inhibition of DUB3, reverted the resistance to targeted therapies.
Identifiants
pubmed: 37372043
pii: antiox12061313
doi: 10.3390/antiox12061313
pmc: PMC10294952
pii:
doi:
Types de publication
Journal Article
Langues
eng
Subventions
Organisme : University of Turin
ID : local funds to A.R., C.D. and S.P
Déclaration de conflit d'intérêts
The authors declare no conflict of interest.
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