title: Abrogation of BRAFV600E-induced senescence by PI3K pathway activation contributes to melanomagenesis.
abstract: Human melanocytic nevi (moles) are benign lesions harboring activated oncogenes, including BRAF. Although this oncogene initially acts mitogenically, eventually, oncogene-induced senescence (OIS) ensues. Nevi can infrequently progress to melanomas, but the mechanistic relationship with OIS is unclear. We show here that PTEN depletion abrogates BRAF(V600E)-induced senescence in human fibroblasts and melanocytes. Correspondingly, in established murine BRAF(V600E)-driven nevi, acute shRNA-mediated depletion of PTEN prompted tumor progression. Furthermore, genetic analysis of laser-guided microdissected human contiguous nevus-melanoma specimens recurrently revealed identical mutations in BRAF or NRAS in adjacent benign and malignant melanocytes. The PI3K pathway was often activated through either decreased PTEN or increased AKT3 expression in melanomas relative to their adjacent nevi. Pharmacologic PI3K inhibition in melanoma cells suppressed proliferation and induced the senescence-associated tumor suppressor p15(INK4B). This treatment also eliminated subpopulations resistant to targeted BRAF(V600E) inhibition. Our findings suggest that a significant proportion of melanomas arise from nevi. Furthermore, these results demonstrate that PI3K pathway activation serves as a rate-limiting event in this setting, acting at least in part by abrogating OIS. The reactivation of senescence features and elimination of cells refractory to BRAF(V600E) inhibition by PI3K inhibition warrants further investigation into the therapeutic potential of simultaneously targeting these pathways in melanoma.
authors.affiliation: Division of Molecular Oncology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
authors.forename: Liesbeth C W
authors.initials: LC
authors.lastname: Vredeveld
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Possik
authors.forename: Marjon A
authors.initials: MA
authors.lastname: Smit
authors.forename: Katrin
authors.initials: K
authors.lastname: Meissl
authors.forename: Chrysiis
authors.initials: C
authors.lastname: Michaloglou
authors.forename: Hugo M
authors.initials: HM
authors.lastname: Horlings
authors.forename: Abderrahim
authors.initials: A
authors.lastname: Ajouaou
authors.forename: Pim C
authors.initials: PC
authors.lastname: Kortman
authors.forename: David
authors.initials: D
authors.lastname: Dankort
authors.forename: Martin
authors.initials: M
authors.lastname: McMahon
authors.forename: Wolter J
authors.initials: WJ
authors.lastname: Mooi
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Peeper
mesh_terms: D019943:Amino Acid Substitution; D049109:Cell Proliferation; D016922:Cellular Senescence; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000378:metabolism; D004789:Enzyme Activation; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D018698:Glutamic Acid / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008544:Melanocytes / Q000378:metabolism / Q000473:pathology; D008545:Melanoma / Q000378:metabolism / Q000473:pathology*; D009506:Nevus / Q000378:metabolism / Q000473:pathology*; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology*; D014633:Valine / Q000235:genetics / Q000378:metabolism
chemical_list: D050762:Cyclin-Dependent Kinase Inhibitor p15; D018698:Glutamic Acid; D019869:Phosphatidylinositol 3-Kinases; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D014633:Valine