Aurora kinase B inhibition reduces the proliferation of metastatic melanoma cells and enhances the response to chemotherapy

Journal of Translational Medicine

Amalia Azzariti⁴  Michele Guida⁵  Stefania Tommasi¹  Stefania Guida²  Sabino Strippoli⁵  Diana A Stolfa⁴  Anna Ferretta³  Rosa M Iacobazzi⁴  Immacolata Maida³  Letizia Sidella⁴  Tiziana Cocco³  Anna E Quatrale⁴  Gabriella Guida³  Letizia Porcelli⁴ 

[1] Molecular Genetics Laboratory, National Cancer Research Centre Istituto Tumori Giovanni Paolo II, Viale O. Flacco,65, Bari, 70124, Italy;Unit of Dermatology and Venereology, University of Bari, P.zza Giulio Cesare, Bari, 70124, Italy;Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari, P.zza Giulio Cesare, Bari, 70124, Italy;Clinical and Preclinical Pharmacology Laboratory, National Cancer Research Centre Istituto Tumori Giovanni Paolo II, Viale O. Flacco,65, Bari, 70124, Italy;Medical Oncology Department, National Cancer Research Centre Istituto Tumori Giovanni Paolo II, Viale O. Flacco,65, Bari, 70124, Italy

关键词: BRAF status;    Nab-paclitaxel;    Vemurafenib;    Barasertib;    Melanoma;   

Others  :  1139246
DOI  :  10.1186/s12967-015-0385-4

 received in 2014-11-13, accepted in 2015-01-08,  发布年份 2015

【 摘 要 】

Background

The poor response to chemotherapy and the brief response to vemurafenib in metastatic melanoma patients, make the identification of new therapeutic approaches an urgent need. Interestingly the increased expression and activity of the Aurora kinase B during melanoma progression suggests it as a promising therapeutic target.

Methods

The efficacy of the Aurora B kinase inhibitor barasertib-HQPA was evaluated in BRAF mutated cells, sensitive and made resistant to vemurafenib after chronic exposure to the drug, and in BRAF wild type cells. The drug effectiveness has been evaluated as cell growth inhibition, cell cycle progression and cell migration. In addition, cellular effectors of drug resistance and response were investigated.

Results

The characterization of the effectors responsible for the resistance to vemurafenib evidenced the increased expression of MITF or the activation of Erk1/2 and p-38 kinases in the newly established cell lines with a phenotype resistant to vemurafenib. The sensitivity of cells to barasertib-HQPA was irrespective of BRAF mutational status. Barasertib-HQPA induced the mitotic catastrophe, ultimately causing apoptosis and necrosis of cells, inhibited cell migration and strongly affected the glycolytic metabolism of cells inducing the release of lactate. In association i) with vemurafenib the gain in effectiveness was found only in BRAF(V600K) cells while ii) with nab-paclitaxel, the combination was more effective than each drug alone in all cells.

Conclusions

These findings suggest barasertib as a new therapeutic agent and as enhancer of chemotherapy in metastatic melanoma treatment.

【 授权许可】

   
2015 Porcelli et al.; licensee BioMed Central.

【 图 表 】

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