Abstract
BackgroundThe 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.MethodsThe 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.ResultsThe 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.ConclusionsThese findings suggest barasertib as a new therapeutic agent and as enhancer of chemotherapy in metastatic melanoma treatment.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-015-0385-4) contains supplementary material, which is available to authorized users.
Highlights
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
Literature data reported the promising opportunity to combine the inhibition of Aurora A kinase with that of BRAF or MEK in BRAF mutated or wild type MM models [13], while no evidence currently exist testing the combination of Aurora kinases inhibitors with chemotherapy in melanoma treatment
Characterization of vemurafenib sensitivity in function of BRAF status Sensitivity to vemurafenib was assessed in a panel of 4 cell lines: LND1 and HBL cells which have BRAF wild type (w.t.) and MBA72 and Hmel-1 cells carrying mutations V600E and V600K in BRAF, both known to be responsible for high responsiveness to vemurafenib in patients at least at the beginning of the therapy [27,28,1,34]
Summary
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. One of recent approach followed by most scientists is to block the MAPK pathway, which is activated in the establishment of resistance to BRAF inhibitors. This therapeutic approach involves the use of MEK inhibitors, but the published results are not as promising as hoped by scientific audience [6]. Literature data reported the promising opportunity to combine the inhibition of Aurora A kinase with that of BRAF or MEK in BRAF mutated or wild type MM models [13], while no evidence currently exist testing the combination of Aurora kinases inhibitors with chemotherapy in melanoma treatment
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
