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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Vemurafenib resistance increases melanoma invasiveness and modulates the tumor microenvironment by MMP-2 upregulation

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Sandri, Silvana ; Faiao-Flores, Fernanda ; Tiago, Manoela ; Pennacchi, Paula Comune ; Massaro, Renato Ramos ; Alves-Fernandes, Debora Kristina ; Berardinelli, Gustavo Noriz ; Evangelista, Adriane Feijo ; Vazquez, Vinicius de Lima ; Reis, Rui Manuel ; Maria-Engler, Silvya Suchi
Total Authors: 11
Document type: Journal article
Source: PHARMACOLOGICAL RESEARCH; v. 111, p. 523-533, SEP 2016.
Web of Science Citations: 19
Abstract

The BRAF(V600E) mutation confers constitutive kinase activity and accounts for >90% of BRAF mutations in melanoma. This genetic alteration is a current therapeutic target; however, the antitumorigenic effects of the BRAF(V600E) inhibitor vemurafenib are short-lived and the majority of patients present tumor relapse in a short period after treatment. Characterization of vemurafenib resistance has been essential to the efficacy of next generation therapeutic strategies. Herein, we found that acute BRAF inhibition induced a decrease in active MMP-2, MT1-MMP and MMP-9, but did not modulate the metalloproteinase inhibitors TIMP-2 or RECK in naive melanoma cells. In vemurafenib-resistant melanoma cells, we observed a lower growth rate and an increase in EGFR phosphorylation followed by the recovery of active MMP-2 expression, a mediator of cancer metastasis. Furthermore, we found a different profile of MMP inhibitor expression, characterized by TIMP-2 downregulation and RECK upregulation. In a 3D spheroid model, the invasion index of vemurafenib-resistant melanoma cells was more evident than in its non-resistant counterpart. We confirmed this pattern in a matrigel invasion assay and demonstrated that use of a matrix metalloproteinase inhibitor reduced the invasion of vemurafenib resistant melanoma cells but not drug naive cells. Moreover, we did not observe a delimited group of cells invading the dermis in vemurafenib-resistant melanoma cells present in a reconstructed skin model. The same MMP-2 and RECK upregulation profile was found in this 3D skin model containing vemurafenib-resistant melanoma cells. Acute vemurafenib treatment induces the disorganization of collagen fibers and consequently, extracellular matrix remodeling, with this pattern observed even after the acquisition of resistance. Altogether, our data suggest that resistance to vemurafenib induces significant changes in the tumor microenvironment mainly by MMP-2 upregulation, with a corresponding increase in cell invasiveness. (C) 2016 Elsevier Ltd. All rights reserved. (AU)

FAPESP's process: 14/24400-0 - In vitro models for pre clinical studies of melanoma Chemoresistant
Grantee:Silvya Stuchi Maria-Engler
Support type: Regular Research Grants
FAPESP's process: 13/05172-4 - Impact of epithelial-mesenchymal transition proteins ín vemurafenib chemoresistant melanoma
Grantee:Fernanda Faião Flores
Support type: Scholarships in Brazil - Post-Doctorate