title: MEK inhibition exhibits efficacy in human and mouse neurofibromatosis tumors.
abstract: Neurofibromatosis type 1 (NF1) patients develop benign neurofibromas and malignant peripheral nerve sheath tumors (MPNST). These incurable peripheral nerve tumors result from loss of NF1 tumor suppressor gene function, causing hyperactive Ras signaling. Activated Ras controls numerous downstream effectors, but specific pathways mediating the effects of hyperactive Ras in NF1 tumors are unknown. We performed cross-species transcriptome analyses of mouse and human neurofibromas and MPNSTs and identified global negative feedback of genes that regulate Ras/Raf/MEK/ERK signaling in both species. Nonetheless, ERK activation was sustained in mouse and human neurofibromas and MPNST. We used a highly selective pharmacological inhibitor of MEK, PD0325901, to test whether sustained Ras/Raf/MEK/ERK signaling contributes to neurofibroma growth in a neurofibromatosis mouse model (Nf1(fl/fl);Dhh-Cre) or in NF1 patient MPNST cell xenografts. PD0325901 treatment reduced aberrantly proliferating cells in neurofibroma and MPNST, prolonged survival of mice implanted with human MPNST cells, and shrank neurofibromas in more than 80% of mice tested. Our data demonstrate that deregulated Ras/ERK signaling is critical for the growth of NF1 peripheral nerve tumors and provide a strong rationale for testing MEK inhibitors in NF1 clinical trials.
authors.affiliation: Children’s Hospital Medical Center, Division of Experimental Hematology and Cancer Biology, 3333 Burnet Ave., M.L.C. 7013, Cincinnati, Ohio 45229, USA.
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Jessen
authors.forename: Shyra J
authors.initials: SJ
authors.lastname: Miller
authors.forename: Edwin
authors.initials: E
authors.lastname: Jousma
authors.forename: Jianqiang
authors.initials: J
authors.lastname: Wu
authors.forename: Tilat A
authors.initials: TA
authors.lastname: Rizvi
authors.forename: Meghan E
authors.initials: ME
authors.lastname: Brundage
authors.forename: David
authors.initials: D
authors.lastname: Eaves
authors.forename: Brigitte
authors.initials: B
authors.lastname: Widemann
authors.forename: Mi-Ok
authors.initials: MO
authors.lastname: Kim
authors.forename: Eva
authors.initials: E
authors.lastname: Dombi
authors.forename: Jessica
authors.initials: J
authors.lastname: Sabo
authors.forename: Atira
authors.initials: A
authors.lastname: Hardiman Dudley
authors.forename: Michiko
authors.initials: M
authors.lastname: Niwa-Kawakita
authors.forename: Grier P
authors.initials: GP
authors.lastname: Page
authors.forename: Marco
authors.initials: M
authors.lastname: Giovannini
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Aronow
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Cripe
authors.forename: Nancy
authors.initials: N
authors.lastname: Ratner
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D002648:Child; D002675:Child, Preschool; D004159:Diphenylamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009368:Neoplasm Transplantation; D009456:Neurofibromatosis 1 / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D015689:Oncogene Protein p21(ras) / Q000235:genetics / Q000378:metabolism; D010524:Peripheral Nervous System Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D059467:Transcriptome / Q000187:drug effects / Q000235:genetics; D014183:Transplantation, Heterologous; D023041:Xenograft Model Antitumor Assays; D048490:raf Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D001549:Benzamides; C506614:mirdametinib; D004159:Diphenylamine; D048490:raf Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D015689:Oncogene Protein p21(ras)