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@ARTICLE{Berberich:148292,
      author       = {A. Berberich$^*$ and L.-M. Schmitt$^*$ and S. Pusch$^*$ and
                      T. Hielscher$^*$ and P. Rübmann$^*$ and N. Hucke$^*$ and P.
                      Latzer$^*$ and B. Heßling$^*$ and D. Lemke$^*$ and T.
                      Kessler$^*$ and M. Platten$^*$ and W. Wick$^*$},
      title        = {c{M}yc and {ERK} activity are associated with resistance to
                      {ALK} inhibitory treatment in glioblastoma.},
      journal      = {Journal of neuro-oncology},
      volume       = {146},
      number       = {1},
      issn         = {1573-7373},
      address      = {Dordrecht [u.a.]},
      publisher    = {Springer Science + Business Media B.V},
      reportid     = {DKFZ-2019-02856},
      pages        = {9-23},
      year         = {2020},
      note         = {2020 Jan;146(1):9-23#EA:B320#LA:B320#},
      abstract     = {Anaplastic lymphoma kinase (ALK) is expressed
                      $in ~ 60\%$ of glioblastomas and conveys tumorigenic
                      functions. Therefore, ALK inhibitory strategies with
                      alectinib are conceivable for patients with glioblastoma.
                      The aims of this preclinical study were to investigate
                      efficacy as well as to understand and potentially overcome
                      primary and acquired resistance mechanisms of alectinib in
                      glioblastoma.Efficacy of alectinib was analyzed dependent on
                      ALK expression in different glioblastoma initiating cells
                      and after lentiviral knockdown of ALK. Alectinib resistant
                      cells were generated by continuous treatment with increasing
                      alectinib doses over 3 months. M-RNA, phospho-protein and
                      protein regulation were analyzed to decipher relevant
                      pathways associated to treatment or resistance and
                      specifically inhibited to evaluate rational salvage
                      therapies.Alectinib reduced clonogenicity and proliferation
                      and induced apoptosis in ALK expressing glioblastoma
                      initiating cells, whereas cells without ALK expression or
                      after ALK depletion via knockdown showed primary resistance
                      against alectinib. High expression of cMyc and activation of
                      the ERK1/2 pathway conferred resistance against alectinib in
                      ALK expressing glioblastoma cells. Pharmacological
                      inhibition of these pathways by cMyc inhibitor or MEK
                      inhibitor, trametinib, overcame alectinib resistance and
                      re-sensitized resistant cells to continued alectinib
                      treatment. The combination of alectinib with radiotherapy
                      demonstrated synergistic effects in inhibition of
                      clonogenicity in non-resistant and alectinib resistant
                      glioblastoma cells.The data offer rationales for alectinib
                      treatment in ALK expressing glioblastoma and for the use of
                      ALK expression status as potential biomarker for alectinib
                      treatment. In addition, the results propose MEK inhibition
                      or radiotherapy as reasonable salvage treatments after
                      acquired alectinib resistance.},
      cin          = {B320 / B300 / C060 / W120 / D170 / HD01},
      ddc          = {610},
      cid          = {I:(DE-He78)B320-20160331 / I:(DE-He78)B300-20160331 /
                      I:(DE-He78)C060-20160331 / I:(DE-He78)W120-20160331 /
                      I:(DE-He78)D170-20160331 / I:(DE-He78)HD01-20160331},
      pnm          = {312 - Functional and structural genomics (POF3-312)},
      pid          = {G:(DE-HGF)POF3-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:31776900},
      doi          = {10.1007/s11060-019-03348-z},
      url          = {https://inrepo02.dkfz.de/record/148292},
}