Proteomic identification of a marker signature for MAPKi resistance in melanoma.
Adult
Aged
Carbamates
/ pharmacology
Cell Adhesion
Cell Line, Tumor
Disease Progression
Drug Resistance, Neoplasm
Epithelial-Mesenchymal Transition
Female
Gene Expression Regulation, Neoplastic
/ drug effects
Humans
Insulin-Like Growth Factor Binding Proteins
/ blood
Male
Melanoma
/ drug therapy
Middle Aged
Protein Interaction Maps
Protein Kinase Inhibitors
/ pharmacology
Proteomics
/ methods
RNA-Binding Proteins
/ metabolism
Sequence Analysis, RNA
Sulfonamides
/ pharmacology
Survival Analysis
Up-Regulation
Vemurafenib
/ pharmacology
BRAF
PTRF
mass spectrometry
melanoma
resistance
Journal
The EMBO journal
ISSN: 1460-2075
Titre abrégé: EMBO J
Pays: England
ID NLM: 8208664
Informations de publication
Date de publication:
01 08 2019
01 08 2019
Historique:
received:
02
12
2016
revised:
15
05
2019
accepted:
22
05
2019
pubmed:
4
7
2019
medline:
24
12
2019
entrez:
4
7
2019
Statut:
ppublish
Résumé
MAPK inhibitors (MAPKi) show outstanding clinical response rates in melanoma patients harbouring BRAF mutations, but resistance is common. The ability of melanoma cells to switch from melanocytic to mesenchymal phenotypes appears to be associated with therapeutic resistance. High-throughput, subcellular proteome analyses and RNAseq on two panels of primary melanoma cells that were either sensitive or resistant to MAPKi revealed that only 15 proteins were sufficient to distinguish between these phenotypes. The two proteins with the highest discriminatory power were PTRF and IGFBP7, which were both highly upregulated in the mesenchymal-resistant cells. Proteomic analysis of CRISPR/Cas-derived PTRF knockouts revealed targets involved in lysosomal activation, endocytosis, pH regulation, EMT, TGFβ signalling and cell migration and adhesion, as well as a significantly reduced invasive index and ability to form spheres in 3D culture. Overexpression of PTRF led to MAPKi resistance, increased cell adhesion and sphere formation. In addition, immunohistochemistry of patient samples showed that PTRF expression levels were a significant biomarker of poor progression-free survival, and IGFBP7 levels in patient sera were shown to be higher after relapse.
Identifiants
pubmed: 31267558
doi: 10.15252/embj.201695874
pmc: PMC6669927
doi:
Substances chimiques
CAVIN1 protein, human
0
Carbamates
0
Insulin-Like Growth Factor Binding Proteins
0
Protein Kinase Inhibitors
0
RNA-Binding Proteins
0
Sulfonamides
0
insulin-like growth factor binding protein-related protein 1
0
Vemurafenib
207SMY3FQT
encorafenib
8L7891MRB6
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e95874Subventions
Organisme : Promedica Stiftung
ID : 1334/M
Pays : International
Organisme : MUW Mobility Grant
Pays : International
Organisme : Comprehensive Cancer Center Forschungsförderung der Initiative Krebsforschung, MedUni Wien
Pays : International
Organisme : Forschungskredit of the University of Zurich
ID : FK-14-032
Pays : International
Organisme : URPP "Translational Cancer Research" Grant
Pays : International
Organisme : Louis Widmer Grant
Pays : International
Organisme : Bürgermeistergrant
Pays : International
Organisme : Verein Hautkrebsforschung
Pays : International
Organisme : Swiss National Science Foundation
ID : PMPDP3_151326
Pays : Switzerland
Organisme : Swiss National Science Foundation
ID : 31003A_166435
Pays : Switzerland
Organisme : Verein für Hautkrebsforschung
Pays : International
Organisme : Hochspezialisierte Medizin Schwerpunkt Immunologie (HSM-2-Immunologie) Schweiz and Krebsliga Schweiz
ID : KLS 3151-02-2013
Pays : International
Organisme : Prof. Bruno Bloch Foundation
Pays : International
Informations de copyright
© 2019 The Authors.
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