PMID- 24996772
OWN - NLM
STAT- MEDLINE
DCOM- 20151214
LR  - 20220316
IS  - 1873-2496 (Electronic)
IS  - 1078-1439 (Linking)
VI  - 33
IP  - 2
DP  - 2015 Feb
TI  - The tyrosine kinase inhibitor nilotinib has antineoplastic activity in prostate 
      cancer cells but up-regulates the ERK survival signal-Implications for targeted 
      therapies.
PG  - 72.e1-7
LID - S1078-1439(14)00206-3 [pii]
LID - 10.1016/j.urolonc.2014.06.001 [doi]
AB  - 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.
CI  - Copyright (c) 2014 Elsevier Inc. All rights reserved.
FAU - Schneider, Meike
AU  - Schneider M
AD  - Department of Urology, University of Heidelberg School of Medicine, Heidelberg, 
      Germany.
FAU - Korzeniewski, Nina
AU  - Korzeniewski N
AD  - Molecular Urooncology, Department of Urology, University of Heidelberg School of 
      Medicine, Heidelberg, Germany.
FAU - Merkle, Konstanze
AU  - Merkle K
AD  - Molecular Urooncology, Department of Urology, University of Heidelberg School of 
      Medicine, Heidelberg, Germany.
FAU - Schuler, Julia
AU  - Schuler J
AD  - Oncotest GmbH, Freiburg, Germany.
FAU - Grullich, Carsten
AU  - Grullich C
AD  - National Center for Tumor Diseases, Heidelberg, Germany.
FAU - Hadaschik, Boris
AU  - Hadaschik B
AD  - Department of Urology, University of Heidelberg School of Medicine, Heidelberg, 
      Germany.
FAU - Hohenfellner, Markus
AU  - Hohenfellner M
AD  - Department of Urology, University of Heidelberg School of Medicine, Heidelberg, 
      Germany.
FAU - Duensing, Stefan
AU  - Duensing S
AD  - 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.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140702
PL  - United States
TA  - Urol Oncol
JT  - Urologic oncology
JID - 9805460
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Pyrimidines)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
RN  - F41401512X (nilotinib)
SB  - IM
MH  - Animals
MH  - Cell Line, Tumor
MH  - Drug Resistance, Neoplasm
MH  - Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors/*metabolism
MH  - Humans
MH  - MAP Kinase Signaling System/*drug effects
MH  - Male
MH  - Mice
MH  - Mice, Mutant Strains
MH  - Prostatic Neoplasms/*drug therapy/enzymology/metabolism
MH  - Protein Kinase Inhibitors/*pharmacology
MH  - Pyrimidines/*pharmacology
MH  - Random Allocation
MH  - Up-Regulation/drug effects
MH  - Xenograft Model Antitumor Assays
OTO - NOTNLM
OT  - Drug resistance
OT  - ERK
OT  - Nilotinib
OT  - Prostate cancer
OT  - Translational therapeutics
EDAT- 2014/07/06 06:00
MHDA- 2015/12/15 06:00
CRDT- 2014/07/06 06:00
PHST- 2013/12/06 00:00 [received]
PHST- 2014/05/08 00:00 [revised]
PHST- 2014/06/02 00:00 [accepted]
PHST- 2014/07/06 06:00 [entrez]
PHST- 2014/07/06 06:00 [pubmed]
PHST- 2015/12/15 06:00 [medline]
AID - S1078-1439(14)00206-3 [pii]
AID - 10.1016/j.urolonc.2014.06.001 [doi]
PST - ppublish
SO  - Urol Oncol. 2015 Feb;33(2):72.e1-7. doi: 10.1016/j.urolonc.2014.06.001. Epub 2014 
      Jul 2.