title: Elucidating distinct roles for NF1 in melanomagenesis.
abstract: BRAF mutations play a well-established role in melanomagenesis; however, without additional genetic alterations, tumor development is restricted by oncogene-induced senescence (OIS). Here, we show that mutations in the NF1 tumor suppressor gene cooperate with BRAF mutations in melanomagenesis by preventing OIS. In a genetically engineered mouse model, Nf1 mutations suppress Braf-induced senescence, promote melanocyte hyperproliferation, and enhance melanoma development. Nf1 mutations function by deregulating both phosphoinositide 3-kinase and extracellular signal-regulated kinase pathways. As such, Nf1/Braf-mutant tumors are resistant to BRAF inhibitors but are sensitive to combined inhibition of mitogen-activated protein/extracellular signal-regulated kinase kinase and mTOR. Importantly, NF1 is mutated or suppressed in human melanomas that harbor concurrent BRAF mutations, NF1 ablation decreases the sensitivity of melanoma cell lines to BRAF inhibitors, and NF1 is lost in tumors from patients following treatment with these agents. Collectively, these studies provide mechanistic insight into how NF1 cooperates with BRAF mutations in melanoma and show that NF1/neurofibromin inactivation may have an impact on responses to targeted therapies.
authors.affiliation: Genetics Division, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Ophélia
authors.initials: O
authors.lastname: Maertens
authors.forename: Bryan
authors.initials: B
authors.lastname: Johnson
authors.forename: Pablo
authors.initials: P
authors.lastname: Hollstein
authors.forename: Dennie T
authors.initials: DT
authors.lastname: Frederick
authors.forename: Zachary A
authors.initials: ZA
authors.lastname: Cooper
authors.forename: Ludwine
authors.initials: L
authors.lastname: Messiaen
authors.forename: Roderick T
authors.initials: RT
authors.lastname: Bronson
authors.forename: Martin
authors.initials: M
authors.lastname: McMahon
authors.forename: Scott
authors.initials: S
authors.lastname: Granter
authors.forename: Keith
authors.initials: K
authors.lastname: Flaherty
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Wargo
authors.forename: Richard
authors.initials: R
authors.lastname: Marais
authors.forename: Karen
authors.initials: K
authors.lastname: Cichowski
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics*; D048708:Cell Growth Processes / Q000235:genetics; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D016514:Genes, Neurofibromatosis 1; D005838:Genotype; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008544:Melanocytes / Q000473:pathology / Q000502:physiology; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D025542:Neurofibromin 1 / Q000172:deficiency / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology; D000077484:Vemurafenib; D023041:Xenograft Model Antitumor Assays
chemical_list: D007211:Indoles; D025542:Neurofibromin 1; D013449:Sulfonamides; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf