title: Metformin and trametinib have synergistic effects on cell viability and tumor growth in NRAS mutant cancer.
abstract: Attempts to directly block the mutant neuroblastoma rat sarcoma oncogene (NRAS) protein, a driving mutation in many cancer types, have been unsuccessful. Current treatments focus on inhibition of different components of NRAS' two main downstream cascades: PI3K/AKT/mTOR and MAPK. Here we test a novel dual therapy combination of metformin and trametinib on a panel of 16 NRAS mutant cell lines, including melanoma cells, melanoma cells with acquired trametinib resistance, lung cancer and neuroblastoma cells. We show that both of the main downstream cascades of NRAS can be blocked by this combination: metformin indirectly inhibits the PI3K/AKT/mTOR pathway and trametinib directly impedes the MAPK pathway. This dual therapy synergistically reduced cell viability in vitro and xenograft tumor growth in vivo. We conclude that metformin and trametinib combinations are effective in preclinical models and may be a possible option for treatment of NRAS mutant cancers.
authors.affiliation: University of California, San Francisco, Department of Dermatology, Mt. Zion Cancer Research Center, San Francisco, CA, USA.|Rudolfstiftung Hospital, Academic Teaching Hospital, Department of Dermatology, Juchgasse, Vienna, Austria.
authors.forename: Igor
authors.initials: I
authors.lastname: Vujic
authors.affiliation: University of California, San Francisco, Department of Dermatology, Mt. Zion Cancer Research Center, San Francisco, CA, USA.|Department of Medical Sciences, Section of Dermatology, University of Turin, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Sanlorenzo
authors.affiliation: University of California, San Francisco, Department of Dermatology, Mt. Zion Cancer Research Center, San Francisco, CA, USA.|Rudolfstiftung Hospital, Academic Teaching Hospital, Department of Dermatology, Juchgasse, Vienna, Austria.
authors.forename: Christian
authors.initials: C
authors.lastname: Posch
authors.affiliation: University of California, San Francisco, Department of Dermatology, Mt. Zion Cancer Research Center, San Francisco, CA, USA.
authors.forename: Rosaura
authors.initials: R
authors.lastname: Esteve-Puig
authors.affiliation: University of California, San Francisco, Department of Dermatology, Mt. Zion Cancer Research Center, San Francisco, CA, USA.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Yen
authors.affiliation: University of California, San Francisco, Department of Dermatology, Mt. Zion Cancer Research Center, San Francisco, CA, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Kwong
authors.affiliation: University of California, San Francisco, Department of Dermatology, Mt. Zion Cancer Research Center, San Francisco, CA, USA.
authors.forename: Aaron
authors.initials: A
authors.lastname: Tsumura
authors.affiliation: University of California, San Francisco, Department of Dermatology, Mt. Zion Cancer Research Center, San Francisco, CA, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Murphy
authors.affiliation: Rudolfstiftung Hospital, Academic Teaching Hospital, Department of Dermatology, Juchgasse, Vienna, Austria.
authors.forename: Klemens
authors.initials: K
authors.lastname: Rappersberger
authors.affiliation: University of California, San Francisco, Department of Dermatology, Mt. Zion Cancer Research Center, San Francisco, CA, USA.
authors.forename: Susana
authors.initials: S
authors.lastname: Ortiz-Urda
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008687:Metformin / Q000494:pharmacology*; D008819:Mice, Nude; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011728:Pyridones / Q000494:pharmacology*; D011744:Pyrimidinones / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D020558:GTP Phosphohydrolases; D008565:Membrane Proteins; D008687:Metformin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D011728:Pyridones; D011744:Pyrimidinones; D058570:TOR Serine-Threonine Kinases; C560077:trametinib; C579846:NRAS protein, human