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@ARTICLE{Berberich:140856,
      author       = {A. Berberich$^*$ and T. Kessler$^*$ and C. Thome$^*$ and S.
                      Pusch$^*$ and T. Hielscher$^*$ and F. Sahm$^*$ and I.
                      Oezen$^*$ and L.-M. Schmitt$^*$ and S. Ciprut$^*$ and N.
                      Hucke$^*$ and P. Rübmann$^*$ and M. Fischer$^*$ and D.
                      Lemke$^*$ and M. Breckwoldt$^*$ and A. von Deimling$^*$ and
                      M. Bendszus and M. Platten$^*$ and W. Wick$^*$},
      title        = {{T}argeting resistance against the {MDM}2 inhibitor
                      {RG}7388 in glioblastoma cells by the {MEK} inhibitor
                      trametinib.},
      journal      = {Clinical cancer research},
      volume       = {25},
      number       = {1},
      issn         = {1557-3265},
      address      = {Philadelphia, Pa. [u.a.]},
      publisher    = {AACR},
      reportid     = {DKFZ-2018-01611},
      pages        = {253-265},
      year         = {2019},
      abstract     = {Resistance is an obstacle of glioma therapy. Despite
                      targeted interventions, tumors harbor primary resistance or
                      become resistant over short course of treatment. This study
                      examined the mouse double minute 2 (MDM2) inhibitor RG7388
                      together with radiotherapy and analyzed strategies to
                      overcome acquired MDM2 inhibitor resistance in
                      glioblastoma.Effects of RG7388 and radiotherapy were
                      analyzed in p53 wild-type glioblastoma cell lines and
                      glioma-initiating cells. RG7388 resistant cells were
                      generated by increasing RG7388 doses over three months.
                      Regulated pathways were investigated by microarray, qRT-PCR
                      and immunoblot analysis and specifically inhibited to
                      evaluate rational salvage therapies at RG7388 resistance.
                      Effects of RG7388 and trametinib treatment were challenged
                      in an orthotopical mouse model with RG7388 resistant U87MG
                      glioblastoma cells.MDM2 inhibition required functional p53
                      and showed synergistic activity with radiotherapy in
                      first-line treatment. Long-term exposure to RG7388 induced
                      resistance by activation of the extracellular
                      signal-regulated kinases 1/2 (ERK1/2) - insulin growth
                      factor binding protein 1 (IGFBP1) signaling cascade, which
                      was specifically overcome by ERK1/2 pathway inhibition with
                      trametinib and knockdown of IGFBP1. Combining trametinib
                      with continued RG7388 treatment enhanced anti-tumor effects
                      at RG7388 resistance in vitro and in vivo.These data provide
                      a rationale for combining RG7388 and radiotherapy as
                      first-line therapy with a specific relevance for tumors
                      insensitive to alkylating standard chemotherapy and for the
                      addition of trametinib to continued RG7388 treatment as
                      salvage therapy after acquired resistance against RG7388 for
                      clinical practice.},
      cin          = {B320 / C060 / B300 / D170 / L101},
      ddc          = {610},
      cid          = {I:(DE-He78)B320-20160331 / I:(DE-He78)C060-20160331 /
                      I:(DE-He78)B300-20160331 / I:(DE-He78)D170-20160331 /
                      I:(DE-He78)L101-20160331},
      pnm          = {312 - Functional and structural genomics (POF3-312)},
      pid          = {G:(DE-HGF)POF3-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:30274984},
      doi          = {10.1158/1078-0432.CCR-18-1580},
      url          = {https://inrepo02.dkfz.de/record/140856},
}