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Molecular alterations associated with acquired resistance to BRAFV600E targeted therapy in melanoma cells

Szász, Istvána,,b; Koroknai, Viktóriaa,,b; Kiss, Tímeaa,,b; Vízkeleti, Lauraa,,b; Ádány, Rózaa,,b; Balázs, Margita,,b

doi: 10.1097/CMR.0000000000000588
Original Articles: Translational Research
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Selective inhibition of the mutant BRAF protein is a highly promising therapeutic approach for melanoma patients carrying the BRAFV600E mutation. Despite the remarkable clinical response, most patients develop resistance and experience tumour regrowth. To clarify the molecular background of BRAF inhibitor resistance, we generated four drug-resistant melanoma cell lines from paired primary/metastatic cell lines using a vemurafenib analogue PLX4720. Three of the resistant cell lines showed decreased proliferation after drug withdrawal, but the proliferation of one cell line (WM278RES) increased notably. Furthermore, we observed opposite phenomena in which a ‘drug holiday’ could not only be beneficial but also contribute to tumour progression. Using genomic and proteomic approaches, we found significantly different alterations between the sensitive and resistant cell lines, some of which have not been reported previously. In addition to several other changes, copy number gains were observed in all resistant cell lines on 8q24.11–q24.12 and 8q21.2. Gene expression analysis showed that most genes upregulated in the resistant cell lines were associated with cell motility and angiogenesis. Increased expression of six proteins (ANGPLT4, EGFR, Endoglin, FGF2, SerpinE1 and VCAM-1) and decreased expression of two proteins (osteopontin and survivin) were observed consistently in all resistant cell lines. In summary, we identified new genomic alterations and characterized the protein expression patterns associated with the resistant phenotype. Although several proteins have been shown to be associated with BRAF resistance, our study is the first to describe the association of VCAM-1 and osteopontin with BRAF resistance.

aDepartment of Preventive Medicine, Division of Biomarker Analysis

bMTA-DE Public Health Research Group, Faculty of Public Health, University of Debrecen, Debrecen, Hungary

Received 28 July 2018 Accepted 21 January 2019

Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website, www.melanomaresearch.com.

Correspondence to Margit Balázs, PhD, DSc, Department of Preventive Medicine, Division of Biomarker Analysis, Faculty of Public Health, University of Debrecen, Kassai str. 26/b, Debrecen 4028, Hungary Tel: + 36 525 12765; fax: + 36 525 12769; e-mail: balazs.margit@sph.unideb.hu

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