title: Loss of NF1 in cutaneous melanoma is associated with RAS activation and MEK dependence.
abstract: Melanoma is a disease characterized by lesions that activate ERK. Although 70% of cutaneous melanomas harbor activating mutations in the BRAF and NRAS genes, the alterations that drive tumor progression in the remaining 30% are largely undefined. Vemurafenib, a selective inhibitor of RAF kinases, has clinical utility restricted to BRAF-mutant tumors. MEK inhibitors, which have shown clinical activity in NRAS-mutant melanoma, may be effective in other ERK pathway-dependent settings. Here, we investigated a panel of melanoma cell lines wild type for BRAF and NRAS to determine the genetic alteration driving their transformation and their dependence on ERK signaling in order to elucidate a candidate set for MEK inhibitor treatment. A cohort of the BRAF/RAS wild type cell lines with high levels of RAS-GTP had loss of NF1, a RAS GTPase activating protein. In these cell lines, the MEK inhibitor PD0325901 inhibited ERK phosphorylation, but also relieved feedback inhibition of RAS, resulting in induction of pMEK and a rapid rebound in ERK signaling. In contrast, the MEK inhibitor trametinib impaired the adaptive response of cells to ERK inhibition, leading to sustained suppression of ERK signaling and significant antitumor effects. Notably, alterations in NF1 frequently co-occurred with RAS and BRAF alterations in melanoma. In the setting of BRAF(V600E), NF1 loss abrogated negative feedback on RAS activation, resulting in elevated activation of RAS-GTP and resistance to RAF, but not MEK, inhibitors. We conclude that loss of NF1 is common in cutaneous melanoma and is associated with RAS activation, MEK-dependence, and resistance to RAF inhibition.
authors.affiliation: Authors' Affiliations: Louis V. Gerstner, Jr. Graduate School of Biomedical Science; Human Oncology and Pathogenesis Program; Departments of Pediatrics, Pathology, and Medicine; Programs in Molecular Pharmacology and Chemistry; Computational Biology; Ludwig Collaborative Lab, Memorial Sloan-Kettering Cancer Center, New York, New York; Department of Medicine, Jonsson Comprehensive Cancer Center, University of California, Los Angeles; Departments of Epidemiology and Biostatistics and Medicine, and the Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California.
authors.forename: Moriah H
authors.initials: MH
authors.lastname: Nissan
authors.forename: Christine A
authors.initials: CA
authors.lastname: Pratilas
authors.forename: Alexis M
authors.initials: AM
authors.lastname: Jones
authors.forename: Ricardo
authors.initials: R
authors.lastname: Ramirez
authors.forename: Helen
authors.initials: H
authors.lastname: Won
authors.forename: Cailian
authors.initials: C
authors.lastname: Liu
authors.forename: Shakuntala
authors.initials: S
authors.lastname: Tiwari
authors.forename: Li
authors.initials: L
authors.lastname: Kong
authors.forename: Aphrothiti J
authors.initials: AJ
authors.lastname: Hanrahan
authors.forename: Zhan
authors.initials: Z
authors.lastname: Yao
authors.forename: Taha
authors.initials: T
authors.lastname: Merghoub
authors.forename: Antoni
authors.initials: A
authors.lastname: Ribas
authors.forename: Paul B
authors.initials: PB
authors.lastname: Chapman
authors.forename: Rona
authors.initials: R
authors.lastname: Yaeger
authors.forename: Barry S
authors.initials: BS
authors.lastname: Taylor
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Schultz
authors.forename: Michael F
authors.initials: MF
authors.lastname: Berger
authors.forename: Neal
authors.initials: N
authors.lastname: Rosen
authors.forename: David B
authors.initials: DB
authors.lastname: Solit
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism; D016514:Genes, Neurofibromatosis 1; D011905:Genes, ras; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008545:Melanoma / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D025542:Neurofibromin 1 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D012878:Skin Neoplasms; D000096142:Cutaneous Malignant Melanoma
chemical_list: D008565:Membrane Proteins; D025542:Neurofibromin 1; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020930:MAP Kinase Kinase Kinases; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human