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Epigenetic Changes of EGFR Have an Important Role in BRAF Inhibitor–Resistant Cutaneous Melanomas
- Source :
- The Journal of investigative dermatology
- Publication Year :
- 2015
- Publisher :
- Elsevier BV, 2015.
-
Abstract
- 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.
- Subjects :
- Proto-Oncogene Proteins B-raf
BRAF inhibitor
Epithelial-Mesenchymal Transition
Skin Neoplasms
EGFR
Dermatology
Biology
Biochemistry
Article
Epigenesis, Genetic
Phosphatidylinositol 3-Kinases
Downregulation and upregulation
Cell Line, Tumor
melanoma
medicine
Humans
metastasis
Neoplasm
Epigenetics
Epithelial–mesenchymal transition
neoplasms
Molecular Biology
PI3K/AKT/mTOR pathway
EGFR inhibitors
epigenetics
Melanoma
Cell Biology
DNA Methylation
medicine.disease
3. Good health
ErbB Receptors
BRAF mutation
Drug Resistance, Neoplasm
DNA methylation
Cancer research
Proto-Oncogene Proteins c-akt
Subjects
Details
- ISSN :
- 0022202X
- Volume :
- 135
- Database :
- OpenAIRE
- Journal :
- Journal of Investigative Dermatology
- Accession number :
- edsair.doi.dedup.....c55ac8e7b71c6d5ce8073670165c03be
- Full Text :
- https://doi.org/10.1038/jid.2014.418