title: Synergistic targeted inhibition of MEK and dual PI3K/mTOR diminishes viability and inhibits tumor growth of canine melanoma underscoring its utility as a preclinical model for human mucosal melanoma.
abstract: Human mucosal melanoma (MM), an uncommon, aggressive and diverse subtype, shares characteristics with spontaneous MM in dogs. Although BRAF and N-RAS mutations are uncommon in MM in both species, the majority of human and canine MM evaluated exhibited RAS/ERK and/or PI3K/mTOR signaling pathway activation. Canine MM cell lines, with varying ERK and AKT/mTOR activation levels reflective of naturally occurring differences in dogs, were sensitive to the MEK inhibitor GSK1120212 and dual PI3K/mTOR inhibitor NVP-BEZ235. The two-drug combination synergistically decreased cell survival in association with caspase 3/7 activation, as well as altered expression of cell cycle regulatory proteins and Bcl-2 family proteins. In combination, the two drugs targeted their respective signaling pathways, potentiating reduction of pathway mediators p-ERK, p-AKT, p-S6, and 4E-BP1 in vitro, and in association with significantly inhibited solid tumor growth in MM xenografts in mice. These findings provide evidence of synergistic therapeutic efficacy when simultaneously targeting multiple mediators in melanoma with Ras/ERK and PI3K/mTOR pathway activation.
authors.affiliation: Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.|Leidos Biomedical Research, Inc., Frederick, MD, USA.
authors.forename: Bih-Rong
authors.initials: BR
authors.lastname: Wei
authors.affiliation: Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Helen T
authors.initials: HT
authors.lastname: Michael
authors.affiliation: Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Charles H C
authors.initials: CH
authors.lastname: Halsey
authors.affiliation: Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Cody J
authors.initials: CJ
authors.lastname: Peer
authors.affiliation: Leidos Biomedical Research, Inc., Frederick, MD, USA.|Frederick National Laboratory for Cancer Research, Center for Advanced Preclinical Research, Frederick, MD, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Adhikari
authors.affiliation: Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Dwyer
authors.affiliation: Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Shelley B
authors.initials: SB
authors.lastname: Hoover
authors.affiliation: Leidos Biomedical Research, Inc., Frederick, MD, USA.|Frederick National Laboratory for Cancer Research, Center for Advanced Preclinical Research, Frederick, MD, USA.
authors.forename: Rajaa
authors.initials: R
authors.lastname: El Meskini
authors.affiliation: Leidos Biomedical Research, Inc., Frederick, MD, USA.|Frederick National Laboratory for Cancer Research, Center for Advanced Preclinical Research, Frederick, MD, USA.
authors.forename: Serguei
authors.initials: S
authors.lastname: Kozlov
authors.affiliation: Leidos Biomedical Research, Inc., Frederick, MD, USA.|Frederick National Laboratory for Cancer Research, Center for Advanced Preclinical Research, Frederick, MD, USA.
authors.forename: Zoe
authors.initials: Z
authors.lastname: Weaver Ohler
authors.affiliation: Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
authors.forename: William D
authors.initials: WD
authors.lastname: Figg
authors.affiliation: Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Glenn
authors.initials: G
authors.lastname: Merlino
authors.affiliation: Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
authors.forename: R Mark
authors.initials: RM
authors.lastname: Simpson
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004285:Dogs; D004357:Drug Synergism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009092:Mucous Membrane / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D020930:MAP Kinase Kinase Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human
keywords: BRAF and NRAS wild type; dactolisib; dog; melanoma; preclinical model; trametinib