期刊
EBIOMEDICINE
卷 39, 期 -, 页码 194-206出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ebiom.2018.12.024
关键词
Vemurafenib; Acquired resistance; Melanoma; uPAR; EGFR
资金
- Associazione Italiana Ricerca sul Cancro (AIRC) [14266]
- Ente Cassa di Risparmio di Firenze
- Italian Foundation for Cancer Research (FIRC)
- Fondazione Veronesi fellowship
- Global Marie Curie Fellowship
Background: BRAE inhibitor (BRAE-I) therapy for melanoma patients harboring the V600E mutation is initially highly effective, but almost all patients relapse within a few months. Understanding the molecular mechanisms behind BRAE-1 responsiveness and acquired resistance is therefore an important issue. Here we assessed the role of urokinase type plasminogen activator receptor (uPAR) as a potentially valuable biomarker in the acquisition of BRAF-1 resistance in V600E mutant melanoma cells. Methods: We examined uPAR and EGER levels by real time PCR and western blot analysis, uPAR loss of function was realized by knocking clown uPAR by RNAi or using M25, a peptide that uncouples uPAR-integrin interaction. We investigated uPAR-I31integrin-EGER association by co-immunoprecipitation and confocal immunofluorescence analysis. Acquired resistance to BRAF-I was generated by chronic exposure of cells to vemurafenib. Findings: We proved that uPAR knockdown in combination with vemurafenib inhibits melanoma cell proliferation to greater extent than either treatment alone causing a decrease in AKT and ERK I /2 phosphorylation. Conversely, we demonstrated that uPAR enforced over-expression results in reduced sensitivity to BRAE inhibition. Moreover, by targeting uPAR and EGFR interaction with an integrin antagonist peptide we restored vemurafenib responsiveness in melanoma resistant cells. Furthermore, we found significant detectable uPAR and EGFR levels in tumor biopsies of 4 relapsed patients. Interpretation: We disclosed an unpredicted mechanism of reduced sensitiveness to BRAF inhibition, driven by elevated levels of uPAR and identified a potential therapeutic strategy to overcome acquired resistance. Funds: Associazione ltaliana Ricerca sul Cancro (A1RC); Ente Cassa di Risparmio di Firenze. (C) 2018 The Authors. Published by Elsevier B.V.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据