title: Combined Inhibition of MEK and Plk1 Has Synergistic Antitumor Activity in NRAS Mutant Melanoma.
abstract: About one-third of cancers harbor activating mutations in rat sarcoma viral oncogene homolog (RAS) oncogenes. In melanoma, aberrant neuroblastoma-RAS (NRAS) signaling fuels tumor progression in about 20% of patients. Current therapeutics for NRAS-driven malignancies barely affect overall survival. To date, pathway interference downstream of mutant NRAS seems to be the most promising approach. In this study, data revealed that mutant NRAS induced Polo-like kinase 1 (Plk1) expression, and pharmacologic inhibition of Plk1 stabilized the size of NRAS mutant melanoma xenografts. The combination of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) and Plk1 inhibitors resulted in a significant growth reduction of NRAS mutant melanoma cells in vitro, and regression of xenografted NRAS mutant melanoma in vivo. Independent cell cycle arrest and increased induction of apoptosis underlies the synergistic effect of this combination. Data further suggest that the p53 signaling pathway is of key importance to the observed therapeutic efficacy. This study provides in vitro, in vivo, and first mechanistic data that an MEK/Plk1 inhibitor combination might be a promising treatment approach for patients with NRAS-driven melanoma. As mutant NRAS signaling is similar across different malignancies, this inhibitor combination could also offer a previously unreported treatment modality for NRAS mutant tumors of other cell origins.
authors.affiliation: University of California San Francisco, Department of Dermatology, Mt. Zion Cancer Research Center, 2340 Sutter Street N461, 94115 San Francisco - USA.|Brigham and Women's Hospital, Harvard Medical School, Department of Dermatology, 77 Avenue Louis Pasteur, 02115 Boston - USA.|The Rudolfstiftung Hospital, Academic Teaching Hospital, Medical University Vienna, Department of Dermatology, Juchgasse 25, 1030 Vienna - Austria.
authors.forename: C
authors.initials: C
authors.lastname: Posch
authors.affiliation: University of Wisconsin, Department of Dermatology, 7418 Wisconsin Institutes for Medical Research, 1111 Highland Ave, Madison, WI 53705 - USA.
authors.forename: B D
authors.initials: BD
authors.lastname: Cholewa
authors.affiliation: University of California San Francisco, Department of Dermatology, Mt. Zion Cancer Research Center, 2340 Sutter Street N461, 94115 San Francisco - USA.|The Rudolfstiftung Hospital, Academic Teaching Hospital, Medical University Vienna, Department of Dermatology, Juchgasse 25, 1030 Vienna - Austria.
authors.forename: I
authors.initials: I
authors.lastname: Vujic
authors.affiliation: University of California San Francisco, Department of Dermatology, Mt. Zion Cancer Research Center, 2340 Sutter Street N461, 94115 San Francisco - USA.|Department of Medical Sciences, Section of Dermatology, University of Turin - Italy.
authors.forename: M
authors.initials: M
authors.lastname: Sanlorenzo
authors.affiliation: University of California San Francisco, Department of Dermatology, Mt. Zion Cancer Research Center, 2340 Sutter Street N461, 94115 San Francisco - USA.
authors.forename: J
authors.initials: J
authors.lastname: Ma
authors.affiliation: University of California San Francisco, Department of Dermatology, Mt. Zion Cancer Research Center, 2340 Sutter Street N461, 94115 San Francisco - USA.
authors.forename: S T
authors.initials: ST
authors.lastname: Kim
authors.affiliation: Brigham and Women's Hospital, Harvard Medical School, Department of Dermatology, 77 Avenue Louis Pasteur, 02115 Boston - USA.
authors.forename: S
authors.initials: S
authors.lastname: Kleffel
authors.affiliation: Brigham and Women's Hospital, Harvard Medical School, Department of Dermatology, 77 Avenue Louis Pasteur, 02115 Boston - USA.
authors.forename: T
authors.initials: T
authors.lastname: Schatton
authors.affiliation: The Rudolfstiftung Hospital, Academic Teaching Hospital, Medical University Vienna, Department of Dermatology, Juchgasse 25, 1030 Vienna - Austria.
authors.forename: K
authors.initials: K
authors.lastname: Rappersberger
authors.affiliation: University of Wisconsin, Department of Dermatology, 7418 Wisconsin Institutes for Medical Research, 1111 Highland Ave, Madison, WI 53705 - USA.
authors.forename: R
authors.initials: R
authors.lastname: Gutteridge
authors.affiliation: University of Wisconsin, Department of Dermatology, 7418 Wisconsin Institutes for Medical Research, 1111 Highland Ave, Madison, WI 53705 - USA.
authors.forename: N
authors.initials: N
authors.lastname: Ahmad
authors.affiliation: University of California San Francisco, Department of Dermatology, Mt. Zion Cancer Research Center, 2340 Sutter Street N461, 94115 San Francisco - USA.
authors.forename: S
authors.initials: S
authors.lastname: Ortiz/Urda
mesh_terms: D000818:Animals; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D011905:Genes, ras / Q000235:genetics; D064593:Heterografts; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000235:genetics / Q000378:metabolism*; D008545:Melanoma / Q000378:metabolism / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D011897:Random Allocation; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology*; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D048369:MAP Kinase Kinase 1; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000097869:Polo-Like Kinase 1