Vemurafenib Resistance Selects for Highly Malignant Brain and Lung-Metastasizing Melanoma Cells

Cancer Lett. 2015 May 28;361(1):86-96. doi: 10.1016/j.canlet.2015.02.041. Epub 2015 Feb 25.

Abstract

V600E being the most common mutation in BRAF, leads to constitutive activation of the MAPK signaling pathway. The majority of V600E BRAF positive melanoma patients treated with the BRAF inhibitor vemurafenib showed initial good clinical responses but relapsed due to acquired resistance to the drug. The aim of the present study was to identify possible biomarkers associated with the emergence of drug resistant melanoma cells. To this end we analyzed the differential gene expression of vemurafenib-sensitive and vemurafenib resistant brain and lung metastasizing melanoma cells. The major finding of this study is that the in vitro induction of vemurafenib resistance in melanoma cells is associated with an increased malignancy phenotype of these cells. Resistant cells expressed higher levels of genes coding for cancer stem cell markers (JARID1B, CD271 and Fibronectin) as well as genes involved in drug resistance (ABCG2), cell invasion and promotion of metastasis (MMP-1 and MMP-2). We also showed that drug-resistant melanoma cells adhere better to and transmigrate more efficiently through lung endothelial cells than drug-sensitive cells. The former cells also alter their microenvironment in a different manner from that of drug-sensitive cells. Biomarkers and molecular mechanisms associated with drug resistance may serve as targets for therapy of drug-resistant cancer.

Keywords: Biomarkers; Cancer stem cells; Metastatic microenvironment; Vemurafenib resistance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism*
  • Blotting, Western
  • Brain Neoplasms / drug therapy
  • Brain Neoplasms / genetics
  • Brain Neoplasms / secondary*
  • Cell Movement / drug effects*
  • Cell Proliferation / drug effects
  • Drug Resistance, Neoplasm / drug effects*
  • Flow Cytometry
  • Gene Expression Profiling
  • Humans
  • Indoles / pharmacology*
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / genetics
  • Lung Neoplasms / secondary*
  • Male
  • Melanoma / drug therapy
  • Melanoma / genetics
  • Melanoma / pathology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology
  • Oligonucleotide Array Sequence Analysis
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / drug effects
  • Sulfonamides / pharmacology*
  • Tumor Cells, Cultured
  • Vemurafenib
  • Xenograft Model Antitumor Assays

Substances

  • Biomarkers, Tumor
  • Indoles
  • RNA, Messenger
  • Sulfonamides
  • Vemurafenib