title: Acute Inhibition of MEK Suppresses Congenital Melanocytic Nevus Syndrome in a Murine Model Driven by Activated NRAS and Wnt Signaling.
abstract: Congenital melanocytic nevus (CMN) syndrome is the association of pigmented melanocytic nevi with extra-cutaneous features, classically melanotic cells within the central nervous system, most frequently caused by a mutation of NRAS codon 61. This condition is currently untreatable and carries a significant risk of melanoma within the skin, brain, or leptomeninges. We have previously proposed a key role for Wnt signaling in the formation of melanocytic nevi, suggesting that activated Wnt signaling may be synergistic with activated NRAS in the pathogenesis of CMN syndrome. Some familial pre-disposition suggests a germ-line contribution to CMN syndrome, as does variability of neurological phenotypes in individuals with similar cutaneous phenotypes. Accordingly, we performed exome sequencing of germ-line DNA from patients with CMN to reveal rare or undescribed Wnt-signaling alterations. A murine model harboring activated NRAS(Q61K) and Wnt signaling in melanocytes exhibited striking features of CMN syndrome, in particular neurological involvement. In the first model of treatment for this condition, these congenital, and previously assumed permanent, features were profoundly suppressed by acute post-natal treatment with a MEK inhibitor. These data suggest that activated NRAS and aberrant Wnt signaling conspire to drive CMN syndrome. Post-natal MEK inhibition is a potential candidate therapy for patients with this debilitating condition.
authors: Institute of Cancer Sciences, University of Glasgow, Glasgow, UK; Beatson Institute for Cancer Research, Glasgow, UK; Current address: Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors: Jeffrey S
authors: JS
authors: Pawlikowski
authors: Institute of Cancer Sciences, University of Glasgow, Glasgow, UK; Beatson Institute for Cancer Research, Glasgow, UK.
authors: Claire
authors: C
authors: Brock
authors: Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors: Sheau-Chiann
authors: SC
authors: Chen
authors: Genetics and Genomic Medicine, UCL Institute of Child Health, London, UK.
authors: Lara
authors: L
authors: Al-Olabi
authors: Beatson Institute for Cancer Research, Glasgow, UK.
authors: Colin
authors: C
authors: Nixon
authors: Beatson Institute for Cancer Research, Glasgow, UK.
authors: Fiona
authors: F
authors: McGregor
authors: Genetics and Genomic Medicine, UCL Institute of Child Health, London, UK.
authors: Simon
authors: S
authors: Paine
authors: GOSgene, UCL Institute of Child Health, London, UK.
authors: Estelle
authors: E
authors: Chanudet
authors: Beatson Institute for Cancer Research, Glasgow, UK.
authors: Wendy
authors: W
authors: Lambie
authors: Institute of Neuroscience and Psychology, University of Glasgow, Glasgow, UK.
authors: William M
authors: WM
authors: Holmes
authors: Institute of Neuroscience and Psychology, University of Glasgow, Glasgow, UK.
authors: James M
authors: JM
authors: Mullin
authors: Department of Veterans Affairs, Vanderbilt University Medical Center, Tennessee Valley Healthcare System, Nashville, Tennessee, USA; Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors: Ann
authors: A
authors: Richmond
authors: Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
authors: Hong
authors: H
authors: Wu
authors: Beatson Institute for Cancer Research, Glasgow, UK.
authors: Karen
authors: K
authors: Blyth
authors: Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
authors: Ayala
authors: A
authors: King
authors: Genetics and Genomic Medicine, UCL Institute of Child Health, London, UK; Pediatric Dermatology, Great Ormond St Hospital, London, UK. Electronic address: v.kinsler@ucl.ac.uk.
authors: Veronica A
authors: VA
authors: Kinsler
authors: Institute of Cancer Sciences, University of Glasgow, Glasgow, UK; Beatson Institute for Cancer Research, Glasgow, UK. Electronic address: p.adams@beatson.gla.ac.uk.
authors: Peter D
authors: PD
authors: Adams
mesh_terms: D000818:Animals; D002648:Child; D004247:DNA / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D020559:Monomeric GTP-Binding Proteins / Q000502:physiology; D009154:Mutation / Q000235:genetics; D009508:Nevus, Pigmented / Q000151:congenital* / Q000378:metabolism / Q000503:physiopathology; D017422:Sequence Analysis, DNA; D015398:Signal Transduction / Q000502:physiology*; D012878:Skin Neoplasms / Q000151:congenital* / Q000378:metabolism / Q000503:physiopathology; D051153:Wnt Proteins / Q000502:physiology*
chemical_list: D008565:Membrane Proteins; D051153:Wnt Proteins; D004247:DNA; D020930:MAP Kinase Kinase Kinases; D020559:Monomeric GTP-Binding Proteins; C586503:Nras protein, mouse