Redirecting resistance evolution in BRAF V600 melanoma by inhibition of the peroxiredoxin-thioredoxin system
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Summary Drug-tolerant persister cells (DTPs) exhibit remarkable cell state heterogeneity and phenotypic evolvability. However, the central question of how DTPs epigenetically coordinate their metabolic flexibility to adapt early to therapeutic stress remains unanswered. We have recently shown that the histone demethylase KDM5B, which is intrinsically expressed in differentiated melanoma DTPs, reprograms the metabolic cell landscape. However, the exact mechanism by which KDM5B affects underlying metabolic enzymes, and whether this reveals new druggable vulnerabilities, remain unknown. By transcriptional and epigenetic profiling of BRAFV600 melanoma cells following KDM5B gene silencing, we discovered a direct molecular axis between the epigenetic regulator KDM5B and the PRDX/TXN ROS detoxification system. This metabolic axis is regulated independently of KDM5B’s demethylase activity. Furthermore, RNAi approaches and the pharmacological inhibition of the PRDX/TXN system led to ROS-induced cell death in differentiated melanoma DTPs and a delay of resistance development to MAPK inhibition. This process was independent of lipid-ROS-driven ferroptosis. Additionally, single-cell transcriptome analyses from pre-clinical melanoma models under continuous MAPK inhibitory treatment demonstrated altered cellular differentiation dynamics, with a reduction in the early evolution into the mesenchymal DTP state under concomitant PRDX inhibition. Interestingly, the degree of melanoma cell state differentiation at the onset of treatment was a major determinant for the transition towards the neural crest-like DTP state. Our study identified a high degree of epigenetic-metabolic connectivity and flexibility within the melanoma DTP pool and urges caution with single redox pathway-targeted strategies for tumor elimination in the future. Prospectively, our results point towards a new resistance targeting strategy for BRAFV600 melanoma patients based on pharmacological re-direction of the evolution of melanoma cell states already at therapy onset. Highlights Transcriptional and epigenetic profiling identified KDM5B as a regulator of the PRDX/TXN-ROS detoxification system PRDX inhibition increases the vulnerability of KDM5B high DTPs to ROS, independent of ferroptosis PRDX inhibition delays resistance to MAPK inhibition in BRAFV600 melanoma cells Longitudinal single-cell transcriptome analysis reveals that PRDX inhibition re-directs early DTP evolution PRDX/TXN gene expression is predictive for melanoma patient survival
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé, mais le titre doit être comparé manuellement.
- Titre Crossref
- Redirecting resistance evolution in <i> BRAF <sup>V600</sup> </i> melanoma by inhibition of the peroxiredoxin-thioredoxin system
- Date Crossref
- 13/03/2025
- Éditeur
- openRxiv
- Type
- posted-content
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Essen University Hospital pays non établi dans la noticeOrganisme public
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German Cancer Research Center pays non établi dans la noticeStructure de recherche
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West Cancer Center pays non établi dans la noticeÉtablissement de santé
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pfm medical (Germany) pays non établi dans la noticeEntreprise
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Deutsches Konsortium für Translationale Krebsforschung pays non établi dans la noticeStructure de recherche
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University of Duisburg-Essen Center for Medical Biotechnology (ZMB) pays non établi dans la noticeUniversité ou école supérieure
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VIB-KU Leuven Center for Cancer Biology pays non établi dans la noticeStructure de recherche
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Ruhrlandklinik pays non établi dans la noticeÉtablissement de santé
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Princess Margaret Cancer Centre pays non établi dans la noticeÉtablissement de santé
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University of Cologne Cologne Excellence Cluster for Cellular Stress Responses in Ageing-Associated Diseases (CECAD) pays non établi dans la noticeUniversité ou école supérieure
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Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases pays non établi dans la noticeStructure de recherche
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University Hospital Cologne pays non établi dans la noticeÉtablissement de santé
Essen University Hospital, German Cancer Research Center et West Cancer Center, avec 9 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.