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@ARTICLE{Shen:142134,
      author       = {J. Shen$^*$ and S. Najafi$^*$ and S. Stäble$^*$ and J.
                      Fabian$^*$ and E. Koeneke$^*$ and F. Kolbinger$^*$ and J.
                      Wrobel$^*$ and B. Meder and M. Distel and T. Heimburg and W.
                      Sippl and M. Jung and H. Peterziel and D. Kranz$^*$ and M.
                      Boutros$^*$ and F. Westermann$^*$ and O. Witt$^*$ and I.
                      Oehme$^*$},
      title        = {{A} kinome-wide {RNA}i screen identifies {ALK} as a target
                      to sensitize neuroblastoma cells for {HDAC}8-inhibitor
                      treatment.},
      journal      = {Cell death and differentiation},
      volume       = {25},
      number       = {12},
      issn         = {1476-5403},
      address      = {London},
      publisher    = {Macmillan},
      reportid     = {DKFZ-2018-02364},
      pages        = {2053 - 2070},
      year         = {2018},
      abstract     = {The prognosis of advanced stage neuroblastoma patients
                      remains poor and, despite intensive therapy, the 5-year
                      survival rate remains less than $50\%.$ We previously
                      identified histone deacetylase (HDAC) 8 as an indicator of
                      poor clinical outcome and a selective drug target for
                      differentiation therapy in vitro and in vivo. Here, we
                      performed kinome-wide RNAi screening to identify genes that
                      are synthetically lethal with HDAC8 inhibitors. These
                      experiments identified the neuroblastoma predisposition gene
                      ALK as a candidate gene. Accordingly, the combination of the
                      ALK/MET inhibitor crizotinib and selective HDAC8 inhibitors
                      (3-6 µM PCI-34051 or 10 µM 20a) efficiently killed
                      neuroblastoma cell lines carrying wildtype ALK
                      (SK-N-BE(2)-C, IMR5/75), amplified ALK (NB-1), and those
                      carrying the activating ALK F1174L mutation (Kelly), and, in
                      cells carrying the activating R1275Q mutation (LAN-5),
                      combination treatment decreased viable cell count. The
                      effective dose of crizotinib in neuroblastoma cell lines
                      ranged from 0.05 µM (ALK-amplified) to 0.8 µM
                      (wildtype ALK). The combinatorial inhibition of ALK and
                      HDAC8 also decreased tumor growth in an in vivo zebrafish
                      xenograft model. Bioinformatic analyses revealed that the
                      mRNA expression level of HDAC8 was significantly correlated
                      with that of ALK in two independent patient cohorts, the
                      Academic Medical Center cohort (n = 88) and the German
                      Neuroblastoma Trial cohort (n = 649), and co-expression
                      of both target genes identified patients with very poor
                      outcome. Mechanistically, HDAC8 and ALK converge at the
                      level of receptor tyrosine kinase (RTK) signaling and their
                      downstream survival pathways, such as ERK signaling.
                      Combination treatment of HDAC8 inhibitor with crizotinib
                      efficiently blocked the activation of growth receptor
                      survival signaling and shifted the cell cycle arrest and
                      differentiation phenotype toward effective cell death of
                      neuroblastoma cell lines, including sensitization of
                      resistant models, but not of normal cells. These findings
                      reveal combined targeting of ALK and HDAC8 as a novel
                      strategy for the treatment of neuroblastoma.},
      cin          = {L101 / B110 / B087 / G340 / L601},
      ddc          = {610},
      cid          = {I:(DE-He78)L101-20160331 / I:(DE-He78)B110-20160331 /
                      I:(DE-He78)B087-20160331 / I:(DE-He78)G340-20160331 /
                      I:(DE-He78)L601-20160331},
      pnm          = {317 - Translational cancer research (POF3-317)},
      pid          = {G:(DE-HGF)POF3-317},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:29515255},
      pmc          = {pmc:PMC6261943},
      doi          = {10.1038/s41418-018-0080-0},
      url          = {https://inrepo02.dkfz.de/record/142134},
}