Journal
JOURNAL OF INVESTIGATIVE DERMATOLOGY
Volume 135, Issue 2, Pages 532-541Publisher
ELSEVIER SCIENCE INC
DOI: 10.1038/jid.2014.418
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Funding
- National Institutes of Health
- National Cancer Institute [PO1 CA029605]
- Ruth and Martin H. Weil Foundation
- Dr Miriam and Sheldon G. Adelson Medical Research Foundation
- [1R01CA167967-01A1]
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BRAF mutations are frequent in cutaneous melanomas, and BRAF inhibitors (BRAFi) have shown remarkable clinical efficacy in BRAF mutant melanoma patients. However, acquired drug resistance can occur rapidly and tumor(s) often progresses thereafter. Various mechanisms of BRAFi resistance have recently been described; however, the mechanism of resistance remains controversial. In this study, we developed BRAFi-resistant melanoma cell lines and found that metastasis-related epithelial to mesenchymal transition properties of BRAFi-resistant cells were enhanced significantly. Upregulation of EGFR was observed in BRAFi-resistant cell lines and patient tumors because of demethylation of EGFR regulatory DNA elements. EGFR induced PI3K/AKT pathway activation in BRAFi-resistant cells through epigenetic regulation. Treatment of EGFR inhibitor was effective in BRAFi-resistant melanoma cell lines. The study demonstrates that EGFR epigenetic activation has important implications in BRAFi resistance in melanoma.
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