title: Epigenetic changes of EGFR have an important role in BRAF inhibitor-resistant cutaneous melanomas.
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.
authors.affiliation: Department of Molecular Oncology, John Wayne Cancer Institute, Santa Monica, California, USA.
authors.forename: Jinhua
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Molecular Oncology, John Wayne Cancer Institute, Santa Monica, California, USA.
authors.forename: Sharon K
authors.initials: SK
authors.lastname: Huang
authors.affiliation: Department of Molecular Oncology, John Wayne Cancer Institute, Santa Monica, California, USA.
authors.forename: Diego M
authors.initials: DM
authors.lastname: Marzese
authors.affiliation: Sequencing Center, John Wayne Cancer Institute, Santa Monica, California, USA.
authors.forename: Sandy C
authors.initials: SC
authors.lastname: Hsu
authors.affiliation: Department of Molecular Oncology, John Wayne Cancer Institute, Santa Monica, California, USA.
authors.forename: Neal P
authors.initials: NP
authors.lastname: Kawas
authors.affiliation: Department of Molecular Oncology, John Wayne Cancer Institute, Santa Monica, California, USA.
authors.forename: Kelly K
authors.initials: KK
authors.lastname: Chong
authors.affiliation: Melanoma Institute Australia and Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Georgina V
authors.initials: GV
authors.lastname: Long
authors.affiliation: Melanoma Institute Australia and Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Menzies
authors.affiliation: Melanoma Institute Australia and Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia; Tissue Pathology and Oncology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Scolyer
authors.affiliation: Department of Cell Research and Immunology, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Sivan
authors.initials: S
authors.lastname: Izraely
authors.affiliation: Department of Cell Research and Immunology, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Orit
authors.initials: O
authors.lastname: Sagi-Assif
authors.affiliation: Department of Cell Research and Immunology, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Isaac P
authors.initials: IP
authors.lastname: Witz
authors.affiliation: Department of Molecular Oncology, John Wayne Cancer Institute, Santa Monica, California, USA; Sequencing Center, John Wayne Cancer Institute, Santa Monica, California, USA. Electronic address: hoond@jwci.org.
authors.forename: Dave S B
authors.initials: DSB
authors.lastname: Hoon
mesh_terms: D045744:Cell Line, Tumor; D019175:DNA Methylation; D019008:Drug Resistance, Neoplasm; D044127:Epigenesis, Genetic; D058750:Epithelial-Mesenchymal Transition; D066246:ErbB Receptors / Q000235:genetics* / Q000502:physiology; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology
chemical_list: D019869:Phosphatidylinositol 3-Kinases; C512478:EGFR protein, human; D066246:ErbB Receptors; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt