title: BRAF inhibitors induce metastasis in RAS mutant or inhibitor-resistant melanoma cells by reactivating MEK and ERK signaling.
abstract: Melanoma is a highly metastatic and lethal form of skin cancer. The protein kinase BRAF is mutated in about 40% of melanomas, and BRAF inhibitors improve progression-free and overall survival in these patients. However, after a relatively short period of disease control, most patients develop resistance because of reactivation of the RAF-ERK (extracellular signal-regulated kinase) pathway, mediated in many cases by mutations in RAS. We found that BRAF inhibition induces invasion and metastasis in RAS mutant melanoma cells through a mechanism mediated by the reactivation of the MEK (mitogen-activated protein kinase kinase)-ERK pathway, increased expression and secretion of interleukin 8, and induction of protease-dependent invasion. These events were accompanied by a cell morphology switch from predominantly rounded to predominantly elongated cells. We also observed similar responses in BRAF inhibitor-resistant melanoma cells. These data show that BRAF inhibitors can induce melanoma cell invasion and metastasis in tumors that develop resistance to these drugs.
authors.affiliation: 1Molecular Oncology Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester M20 4BX, UK.
authors.forename: Berta
authors.initials: B
authors.lastname: Sanchez-Laorden
authors.forename: Amaya
authors.initials: A
authors.lastname: Viros
authors.forename: Maria Romina
authors.initials: MR
authors.lastname: Girotti
authors.forename: Malin
authors.initials: M
authors.lastname: Pedersen
authors.forename: Grazia
authors.initials: G
authors.lastname: Saturno
authors.forename: Alfonso
authors.initials: A
authors.lastname: Zambon
authors.forename: Dan
authors.initials: D
authors.lastname: Niculescu-Duvaz
authors.forename: Samra
authors.initials: S
authors.lastname: Turajlic
authors.forename: Andrew
authors.initials: A
authors.lastname: Hayes
authors.forename: Martin
authors.initials: M
authors.lastname: Gore
authors.forename: James
authors.initials: J
authors.lastname: Larkin
authors.forename: Paul
authors.initials: P
authors.lastname: Lorigan
authors.forename: Martin
authors.initials: M
authors.lastname: Cook
authors.forename: Caroline
authors.initials: C
authors.lastname: Springer
authors.forename: Richard
authors.initials: R
authors.lastname: Marais
mesh_terms: D000818:Animals; D015153:Blotting, Western; D048430:Cell Shape / Q000502:physiology; D004121:Dimethyl Sulfoxide; D019008:Drug Resistance, Neoplasm; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D016209:Interleukin-8 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008545:Melanoma / Q000503:physiopathology*; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000503:physiopathology*; D009362:Neoplasm Metastasis / Q000503:physiopathology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D012878:Skin Neoplasms / Q000503:physiopathology*; D018709:Statistics, Nonparametric; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D007211:Indoles; D016209:Interleukin-8; C528407:PLX 4720; D013449:Sulfonamides; D048493:Proto-Oncogene Proteins B-raf; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras); D004121:Dimethyl Sulfoxide