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.
Highlights
Aurora 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
Melanoma cell exposure to B-RAF, MEK and AurkA inhibitors A375 (BRAFV600E) cell proliferation rates were assessed upon exposure to the different inhibitor drugs alone and in combination
AurkA inhibitor in combination with B-RAF inhibitor and as a triple combination with B-RAF plus MEK inhibitors reduced cell proliferation rate, it was not very effective on cell proliferation rate, as single agent (Figure 1A). This suggests combined B-RAF/AurkA inhibition might be an alternative to B-RAF/MEK inhibition and that triple B-RAF/MEK/AurkA inhibitor therapy could be considered as a therapeutic option
Summary
Aurora 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. Gene mutations in the RAS/RAF/MEK/ERK or mitogen-activated protein kinase (MAPK) pathway have been found to be highly prevalent in melanomas. The most frequent activating mutation (V600E-B-RAF) has been found in exon 15 and results in the substitution of valine for glutamic acid at position 600 of the BRAF protein [3,4]. This mutation represents around 90% of BRAF mutations described in melanoma and occurs in approximately 50% of melanoma cases [5]. Molecular alterations in the c-KIT and GNαQ genes have been described, primarily in mucosal and uveal melanoma subtypes, respectively [10]
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