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Generation of human melanoma cells resistant to PLX4032, a BRAF inhibitor, evaluation of metalloproteinase activity and the process of invasion

Grant number: 13/04080-9
Support type:Scholarships in Brazil - Scientific Initiation
Effective date (Start): May 01, 2013
Effective date (End): April 30, 2014
Field of knowledge:Biological Sciences - Morphology
Principal Investigator:Silvya Stuchi Maria-Engler
Grantee:Patricia Baltrukonis Bucci Casari
Home Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Metastatic melanoma is considered to be one of the most aggressive skin tumors and of poor prognosis for patients. It is also recognized as a heterogeneous disease and with a highly complex etiology, considering the profile of gene mutations. Understanding these molecular changes has a major role in the development of new drugs that act specifically on mutations related to tumor type. Accordingly, therapy for melanoma had a great advance due to the development of a molecule which inhibits protein BRAFV600E, result of the most prevalent mutations in melanoma, characterized by the exchange of a glutamic acid by a valine. This mutation is associated with activation of one of the family members of the mitogen-activated protein kinases (MAPK), which among its functions is the control of proliferation, apoptosis and cell migration. The use of the inhibitor of BRAFV600E, the PLX 4032 (Vemurafenib), orally, causes a significant reduction in metastatic sites and an increase of about 16 months of overall survival compared to that promoted by dacarbamazina, that is around 10 months. However, in case of recurrence of melanoma, patients treated with PLX 4032 were resistant to the drug and the tumor had relapsed more aggressively. Among the mechanisms involved in tumor resistance to PLX 4032 can be mentioned alternative activation kinase phosphatidyl inositol-3 (PI3K), the dimer BRAF-CRAF, overexpression of receptor platelet growth factor (PDGFR) among others. This work aims to generate in vitro cell in BRAFV600E mutated resistant PLX 4032, assess the activity of matrix metalloproteinases (MMPs) and invasion of these cells compared to non-resistant (parental).