Vemurafenib resistance selects for highly malignant brain and lung-metastasizing melanoma cells

Inna Zubrilov, Orit Sagi-Assif, Sivan Izraely, Tsipi Meshel, Shlomit Ben-Menahem, Ravit Ginat, Metsada Pasmanik-Chor, Clara Nahmias, Pierre Olivier Couraud, Dave S.B. Hoon, Isaac P. Witz*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

43 Scopus citations

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.

Original languageEnglish
Pages (from-to)86-96
Number of pages11
JournalCancer Letters
Volume361
Issue number1
DOIs
StatePublished - 28 May 2015

Funding

FundersFunder number
Dr. Miriam and Sheldon G. Adelson Medical Research Foundation04-7023433

    Keywords

    • Biomarkers
    • Cancer stem cells
    • Metastatic microenvironment
    • Vemurafenib resistance

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