title: The tyrosine kinase inhibitor nilotinib has antineoplastic activity in prostate cancer cells but up-regulates the ERK survival signal-Implications for targeted therapies.
abstract: BACKGROUND
  Novel therapeutic options beyond hormone ablation and chemotherapy are urgently needed for patients with advanced prostate cancer. Tyrosine kinase inhibitors (TKIs) are an attractive option as advanced prostate cancers show a highly altered phosphotyrosine proteome. However, despite favorable initial clinical results, the combination of the TKI dasatinib with docetaxel did not result in improved patient survival for reasons that are not known in detail.
  
  
  METHODS
  The National Cancer Institute-Approved Oncology Drug Set II was used in a phenotypic drug screen to identify novel compounds with antineoplastic activity in prostate cancer cells. Validation experiments were carried out in vitro and in vivo.
  
  
  RESULTS
  We identified the TKI nilotinib as a novel compound with antineoplastic activity in hormone-refractory prostate cancer cells. However, further analyses revealed that treatment with nilotinib was associated with a significant up-regulation of the phospho-extracellular-signal-regulated kinases (ERK) survival signal. ERK blockade alone led to a significant antitumoral effect and enhanced the cytotoxicity of nilotinib when used in combination.
  
  
  CONCLUSIONS
  Our findings underscore that TKIs, such as nilotinib, have antitumoral activity in prostate cancer cells but that survival signals, such as ERK up-regulation, may mitigate their effectiveness. ERK blockade alone or in combination with TKIs may represent a promising therapeutic strategy in advanced prostate cancer.
authors.affiliation: Department of Urology, University of Heidelberg School of Medicine, Heidelberg, Germany.
authors.forename: Meike
authors.initials: M
authors.lastname: Schneider
authors.affiliation: Molecular Urooncology, Department of Urology, University of Heidelberg School of Medicine, Heidelberg, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Korzeniewski
authors.affiliation: Molecular Urooncology, Department of Urology, University of Heidelberg School of Medicine, Heidelberg, Germany.
authors.forename: Konstanze
authors.initials: K
authors.lastname: Merkle
authors.affiliation: Oncotest GmbH, Freiburg, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Schüler
authors.affiliation: National Center for Tumor Diseases, Heidelberg, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Grüllich
authors.affiliation: Department of Urology, University of Heidelberg School of Medicine, Heidelberg, Germany.
authors.forename: Boris
authors.initials: B
authors.lastname: Hadaschik
authors.affiliation: Department of Urology, University of Heidelberg School of Medicine, Heidelberg, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Hohenfellner
authors.affiliation: Department of Urology, University of Heidelberg School of Medicine, Heidelberg, Germany; Molecular Urooncology, Department of Urology, University of Heidelberg School of Medicine, Heidelberg, Germany. Electronic address: stefan.duensing@med.uni-heidelberg.de.
authors.forename: Stefan
authors.initials: S
authors.lastname: Duensing
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011897:Random Allocation; D015854:Up-Regulation / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D048049:Extracellular Signal-Regulated MAP Kinases; C498826:nilotinib
keywords: Drug resistance; ERK; Nilotinib; Prostate cancer; Translational therapeutics