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Discoidin Domain Receptor 2 orchestrates melanoma resistance combining phenotype switching and proliferation

Combined therapy with anti-BRAF plus anti-MEK is currently used as first-line treatment of patients with metastatic melanomas harboring the somatic BRAF V600E mutation. However, the main issue with targeted therapy is the acquisition of tumor cell resistance. In a majority of resistant melanoma cell...

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Published in:Oncogene 2022-04, Vol.41 (18), p.2571-2586
Main Authors: Sala, Margaux, Allain, Nathalie, Moreau, Mélanie, Jabouille, Arnaud, Henriet, Elodie, Abou-Hammoud, Aya, Uguen, Arnaud, Di-Tommaso, Sylvaine, Dourthe, Cyril, Raymond, Anne-Aurélie, Dupuy, Jean-William, Gerard, Emilie, Dugot-Senant, Nathalie, Rousseau, Benoit, Merlio, Jean-Phillipe, Pham-Ledart, Anne, Vergier, Béatrice, Tartare-Deckert, Sophie, Moreau, Violaine, Saltel, Frédéric
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cited_by cdi_FETCH-LOGICAL-c412t-f2e6f4280dfc5553bb3b4cedda9c6ec3d639b1c5af668cbe7be61eecda317fad3
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container_end_page 2586
container_issue 18
container_start_page 2571
container_title Oncogene
container_volume 41
creator Sala, Margaux
Allain, Nathalie
Moreau, Mélanie
Jabouille, Arnaud
Henriet, Elodie
Abou-Hammoud, Aya
Uguen, Arnaud
Di-Tommaso, Sylvaine
Dourthe, Cyril
Raymond, Anne-Aurélie
Dupuy, Jean-William
Gerard, Emilie
Dugot-Senant, Nathalie
Rousseau, Benoit
Merlio, Jean-Phillipe
Pham-Ledart, Anne
Vergier, Béatrice
Tartare-Deckert, Sophie
Moreau, Violaine
Saltel, Frédéric
description Combined therapy with anti-BRAF plus anti-MEK is currently used as first-line treatment of patients with metastatic melanomas harboring the somatic BRAF V600E mutation. However, the main issue with targeted therapy is the acquisition of tumor cell resistance. In a majority of resistant melanoma cells, the resistant process consists in epithelial-to-mesenchymal transition (EMT). This process called phenotype switching makes melanoma cells more invasive. Its signature is characterized by MITF low, AXL high, and actin cytoskeleton reorganization through RhoA activation. In parallel of this phenotype switching phase, the resistant cells exhibit an anarchic cell proliferation due to hyper-activation of the MAP kinase pathway. We show that a majority of human melanoma overexpress discoidin domain receptor 2 (DDR2) after treatment. The same result was found in resistant cell lines presenting phenotype switching compared to the corresponding sensitive cell lines. We demonstrate that DDR2 inhibition induces a decrease in AXL expression and reduces stress fiber formation in resistant melanoma cell lines. In this phenotype switching context, we report that DDR2 control cell and tumor proliferation through the MAP kinase pathway in resistant cells in vitro and in vivo. Therefore, inhibition of DDR2 could be a new and promising strategy for countering this resistance mechanism.
doi_str_mv 10.1038/s41388-022-02266-1
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identifier ISSN: 0950-9232
ispartof Oncogene, 2022-04, Vol.41 (18), p.2571-2586
issn 0950-9232
1476-5594
language eng
recordid cdi_hal_primary_oai_HAL_inserm_03791558v1
source Nexis UK; Springer Nature
subjects 13/1
13/106
13/109
13/2
13/51
13/89
13/95
14/19
14/34
14/35
631/67/1059/2326
631/67/1813/1634
631/80/86
64/60
82/51
82/58
Actin
Apoptosis
Axl protein
Cell Biology
Cell Line, Tumor
Cell Proliferation
Cell Proliferation - genetics
Cytoskeleton
Discoidin Domain Receptor 2
Discoidin Domain Receptor 2 - genetics
Drug Resistance, Neoplasm
Drug Resistance, Neoplasm - genetics
Genotype & phenotype
Human Genetics
Humans
Internal Medicine
Kinases
Life Sciences
MAP kinase
Medicine
Medicine & Public Health
Melanoma
Melanoma - drug therapy
Melanoma - genetics
Melanoma - metabolism
Mesenchyme
Metastases
Oncology
Phenotype
Phenotypes
Protein Kinase Inhibitors
Protein Kinase Inhibitors - pharmacology
Proto-Oncogene Proteins B-raf
RhoA protein
Tumors
title Discoidin Domain Receptor 2 orchestrates melanoma resistance combining phenotype switching and proliferation
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