Volume 13 Supplement 1

Melanoma Bridge 2014: meeting abstracts

Open Access

AurkA inhibitors enhance the effects of B-RAF and MEK inhibitors in melanoma treatment

  • Emilia Caputo1,
  • Roberta Miceli2,
  • Maria L. Motti3,
  • Rosarita Taté1,
  • Federica Fratangelo2,
  • Gerardo Botti2,
  • Nicola Mozzillo2,
  • Maria V Carriero2,
  • Ernesta Cavalcanti2,
  • Giuseppe Palmieri4,
  • Gennaro Ciliberto2,
  • Giuseppe Pirozzi2 and
  • Paolo A Ascierto2
Journal of Translational Medicine201513(Suppl 1):P1

https://doi.org/10.1186/1479-5876-13-S1-P1

Published: 15 January 2015

Background

Aurora Kinase A (AurkA), one of the key regulators of M phase progression, is over-expressed in melanoma and has been observed to limit tumor growth [1, 2]. The potential use of this molecule as target for biological therapy in melanoma has been examined.

Materials and methods

A375mel (BRAFV600E) melanoma cell line was used in this study. The cell line was exposed to B-RAF inhibitor (GSK2118436), MEK inhibitor (GSK1120212) and AurkA inhibitor (MLN8054) as single agents or in various combinations (B-RAF plus AurkA inhibitor, MEK plus AurkA inhibitor) or in triple combination (B-RAF plus MEK plus AurkA inhibitor).

The effects on the cell growth of drugs, used as single agents and as different combinations, were examined by the xCELLigence technology. Total protein extracts were examined for p53 and c-myc protein expression by Western Blot analysis. The drug’s efficacy was also tested by using a 3D-human melanoma skin reconstruction model.

Results

A375 (BRAFV600E) melanoma cells treatment with AurkA inhibitors in combination with B-RAF and/or MEK inhibitors alone and/or with both B-RAF/MEK inhibitors, increased the anti-tumor efficacy of the drugs than given as single agents.

The AurkA inhibitors enhancing anti-melanoma effect on B-RAF and MEK inhibitors was furthermore confirmed in a 3D-human melanoma model, where it was restricted to a melanoma cell sub-population localized at epithelial/dermal junction site. 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.

Conclusions

These findings provide new prospects for melanoma research. For the first time, based on these results, it was observed that the triple combination treatment was more efficacious as anti-melanoma therapy. Interesting, the treatment was efficacious only on polygonal-shaped melanoma cells present at the epidermal/dermal junction site as small nests, while spindle-shaped melanoma cells present in the dermal stratum remained alive and proliferating. This finding suggested that these cells may account of the drug resistance and so be responsible of disease recurrence later on. Molecular characterization of these dermal cells may be critical for the development of novel therapeutic strategies.

Authors’ Affiliations

(1)
Institute of Genetics and Biophysics –I.G.B., A. Buzzati-Traverso–, CNR
(2)
Istituto Nazionale Tumori Fondazione G. Pascale
(3)
Dipartimento di Scienze Motorie e del Benessere, Università di Napoli ‘Parthenope’
(4)
Unit of Cancer Genetics, Institute of Biomolecular Chemistry (ICB-CNR)

References

  1. Vader G, Lens SM: The Aurora kinase family in cell division and cancer. Biochim Biophys Acta. 2008, 1786: 60-72.PubMedGoogle Scholar
  2. Nikonova AS, Astsaturov I, Serebriiskii IG, Dunbrack RL, Golemis EA: Aurora A kinase (AURKA) in normal and pathological cell division. Cell Mol Life Sci. 2013, 70: 661-687. 10.1007/s00018-012-1073-7.PubMed CentralView ArticlePubMedGoogle Scholar

Copyright

© Caputo et al; licensee BioMed Central Ltd. 2015

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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