title: Aurora kinase B inhibition reduces the proliferation of metastatic melanoma cells and enhances the response to chemotherapy.
abstract: 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.
authors.affiliation: Clinical and Preclinical Pharmacology Laboratory, National Cancer Research Centre Istituto Tumori Giovanni Paolo II, Viale O. Flacco,65, 70124, Bari, Italy. porcelli.letizia@gmail.com.
authors.forename: Letizia
authors.initials: L
authors.lastname: Porcelli
authors.affiliation: Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari, P.zza Giulio Cesare, 70124, Bari, Italy. gabriella.guida@uniba.it.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Guida
authors.affiliation: Clinical and Preclinical Pharmacology Laboratory, National Cancer Research Centre Istituto Tumori Giovanni Paolo II, Viale O. Flacco,65, 70124, Bari, Italy. annaelisa.quatrale@gmail.com.
authors.forename: Anna E
authors.initials: AE
authors.lastname: Quatrale
authors.affiliation: Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari, P.zza Giulio Cesare, 70124, Bari, Italy. tizianamaria.cocco@uniba.it.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Cocco
authors.affiliation: Clinical and Preclinical Pharmacology Laboratory, National Cancer Research Centre Istituto Tumori Giovanni Paolo II, Viale O. Flacco,65, 70124, Bari, Italy. letizia.sidella@gmail.com.
authors.forename: Letizia
authors.initials: L
authors.lastname: Sidella
authors.affiliation: Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari, P.zza Giulio Cesare, 70124, Bari, Italy. immacolata.maida@uniba.it.
authors.forename: Immacolata
authors.initials: I
authors.lastname: Maida
authors.affiliation: Clinical and Preclinical Pharmacology Laboratory, National Cancer Research Centre Istituto Tumori Giovanni Paolo II, Viale O. Flacco,65, 70124, Bari, Italy. rosamaria.iacobazzi@uniba.it.
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Iacobazzi
authors.affiliation: Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari, P.zza Giulio Cesare, 70124, Bari, Italy. anna.ferretta@uniba.it.
authors.forename: Anna
authors.initials: A
authors.lastname: Ferretta
authors.affiliation: Clinical and Preclinical Pharmacology Laboratory, National Cancer Research Centre Istituto Tumori Giovanni Paolo II, Viale O. Flacco,65, 70124, Bari, Italy. dastolfa@gmail.com.
authors.forename: Diana A
authors.initials: DA
authors.lastname: Stolfa
authors.affiliation: Medical Oncology Department, National Cancer Research Centre Istituto Tumori Giovanni Paolo II, Viale O. Flacco,65, 70124, Bari, Italy. strippoli.sabino@libero.it.
authors.forename: Sabino
authors.initials: S
authors.lastname: Strippoli
authors.affiliation: Unit of Dermatology and Venereology, University of Bari, P.zza Giulio Cesare, 70124, Bari, Italy. stefania.guida@alice.it.
authors.forename: Stefania
authors.initials: S
authors.lastname: Guida
authors.affiliation: Molecular Genetics Laboratory, National Cancer Research Centre Istituto Tumori Giovanni Paolo II, Viale O. Flacco,65, 70124, Bari, Italy. s.tommasi@oncologico.bari.it.
authors.forename: Stefania
authors.initials: S
authors.lastname: Tommasi
authors.affiliation: Medical Oncology Department, National Cancer Research Centre Istituto Tumori Giovanni Paolo II, Viale O. Flacco,65, 70124, Bari, Italy. micguida@libero.it.
authors.forename: Michele
authors.initials: M
authors.lastname: Guida
authors.affiliation: Clinical and Preclinical Pharmacology Laboratory, National Cancer Research Centre Istituto Tumori Giovanni Paolo II, Viale O. Flacco,65, 70124, Bari, Italy. a.azzariti@oncologico.bari.it.
authors.forename: Amalia
authors.initials: A
authors.lastname: Azzariti
mesh_terms: D000418:Albumins / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D064107:Aurora Kinase B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D053144:Cell Nucleus Shape / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005110:Extracellular Space / Q000378:metabolism; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology*; D008938:Mitosis / Q000187:drug effects; D009336:Necrosis; D009362:Neoplasm Metastasis; D010755:Organophosphates / Q000494:pharmacology / Q000627:therapeutic use; D017239:Paclitaxel / Q000494:pharmacology / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: C520255:130-nm albumin-bound paclitaxel; C520647:2-((3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)(ethyl)amino)ethyl dihydrogen phosphate; D000418:Albumins; D010755:Organophosphates; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C531556:AZD 1152-HQPA; D019344:Lactic Acid; D064107:Aurora Kinase B; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D017239:Paclitaxel