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

摘要: 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 inhibitor vemurafenib are short-lived majority patients present tumor relapse short period after treatment. Characterization resistance has been essential to efficacy next generation strategies. Herein, we found that acute inhibition induced decrease active MMP-2, MT1-MMP MMP-9, but did not modulate metalloproteinase inhibitors TIMP-2 or RECK naive melanoma cells. In vemurafenib-resistant cells, observed lower growth rate an increase EGFR phosphorylation followed by recovery MMP-2 expression, mediator cancer metastasis. Furthermore, different profile MMP characterized downregulation upregulation. 3D spheroid model, invasion index cells was more evident than its non-resistant counterpart. We confirmed this pattern matrigel assay demonstrated use matrix reduced resistant drug Moreover, observe delimited group invading dermis reconstructed skin model. same upregulation model containing Acute treatment induces disorganization collagen fibers consequently, extracellular remodeling, with even acquisition resistance. Altogether, our data suggest significant changes microenvironment mainly upregulation, corresponding cell invasiveness.