AurkA inhibitors enhance the effects of B-RAF and MEK inhibitors in melanoma treatment (Articolo in rivista)

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  • AurkA inhibitors enhance the effects of B-RAF and MEK inhibitors in melanoma treatment (Articolo in rivista) (literal)
Anno
  • 2014-01-01T00:00:00+01:00 (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#doi
  • 10.1186/s12967-014-0216-z (literal)
Alternative label
  • Caputo, Emilia; Miceli, Roberta; Motti, Maria Letizia; Tate, Rosarita; Fratangelo, Federica; Botti, Gerardo; Mozzillo, Nicola; Carriero, Maria Vincenza; Cavalcanti, Ernesta; Palmieri, Giuseppe; Ciliberto, Gennaro; Pirozzi, Giuseppe; Ascierto, Paolo Antonio (2014)
    AurkA inhibitors enhance the effects of B-RAF and MEK inhibitors in melanoma treatment
    in Journal of translational medicine (Online)
    (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#autori
  • Caputo, Emilia; Miceli, Roberta; Motti, Maria Letizia; Tate, Rosarita; Fratangelo, Federica; Botti, Gerardo; Mozzillo, Nicola; Carriero, Maria Vincenza; Cavalcanti, Ernesta; Palmieri, Giuseppe; Ciliberto, Gennaro; Pirozzi, Giuseppe; Ascierto, Paolo Antonio (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#numeroVolume
  • 12 (literal)
Rivista
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#pagineTotali
  • 9 (literal)
Note
  • ISI Web of Science (WOS) (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#affiliazioni
  • Institute of Genetics and Biophysics-I.G.B., A. Buzzati-Traverso-, CNR, Via Pietro Castellino, 111, Naples, I-80131, Italy Istituto Nazionale Tumori Fondazione G. Pascale, Via M. Semmola, Naples, I-80131, Italy Dipartimento di Scienze Motorie e del Benessere, Università degli Studi di Napoli 'Parthenope', Via Ammiraglio Ferdinando Acton, 38, Naples, I-80133, Italy Unit of Cancer Genetics, Institute of Biomolecular Chemistry (ICB-CNR), Traversa La Crucca, 3 - Baldinca Li Punti, Sassari, I-07100, Italy (literal)
Titolo
  • AurkA inhibitors enhance the effects of B-RAF and MEK inhibitors in melanoma treatment (literal)
Abstract
  • BackgroundAurora kinase A (AurkA) is over-expressed in melanoma and its inhibition has been observed to limit tumor growth, suggesting a potential role in melanoma treatment.MethodsA human melanoma cell line with the B-RAF (V600E) mutation (A375mel) was exposed to B-RAF inhibitor (GSK2118436), MEK inhibitor (GSK1120212) and AurkA inhibitor (MLN8054) as single agents or in various combinations (BRAF plus AurkA inhibitor, MEK plus AurkA inhibitor or triple combination BRAF plus MEK plus AurkA inhibitor). Cell proliferation was assessed using xCELLigence technology. Total protein extracts were examined for p53 and c-Myc protein expression by Western blot analysis. Drug anti-tumor effects were further assessed using a 3D-human melanoma skin reconstruction model, in which tissues were incubated with serum-free medium containing control, B-RAF plus MEK inhibitor, MEK plus AurkA inhibitor or the triple combination.ResultsAurkA inhibitor plus B-RAF inhibitor, AurkA inhibitor plus MEK inhibitor or triple combination had a markedly greater anti-proliferative effect on A375 (BRAFV600E) melanoma cells than single agents. In the 3D human skin model, the triple combination had a greater anti-tumor effect at the epidermal/dermal junction than control or either double combination. However, S-100 and Ki-67 positively stained spindle-shaped cells were detected in the dermal stratum, suggesting the presence of alive and proliferating melanoma cells.ConclusionsThese findings provide new prospects for melanoma research, including combined B-RAF/AurkA inhibition for B-RAF mutated melanomas and MEK/AurkA inhibitor combination for patients without B-RAF mutations. Moreover, for the first time, we have shown that a B-RAF, MEK and AurkA inhibitor triple drug combination offers increased efficacy against melanoma cell growth and might be considered as a potential treatment strategy for enhancing clinical response in melanoma. However, although this triple drug combination was more effective at the epidermal/dermal junction, the suggested presence of alive and proliferating melanoma cells in the dermal stratum could result in drug resistance and disease recurrence. Molecular characterization of these dermal cells may be critical for the development of novel therapeutic strategies. (literal)
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