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@ARTICLE{Heidler:148283,
      author       = {C. L. Heidler and E. K. Roth and M. Thiemann and C.
                      Blattmann$^*$ and R. Lopez Perez$^*$ and P. E. Huber$^*$ and
                      M. Kovac and B. Amthor and G. Neu-Yilik and A. E. Kulozik},
      title        = {{P}rexasertib ({LY}2606368) reduces clonogenic survival by
                      inducing apoptosis in primary patient-derived osteosarcoma
                      cells and synergizes with cisplatin and talazoparib.},
      journal      = {International journal of cancer},
      volume       = {147},
      number       = {4},
      issn         = {1097-0215},
      address      = {Bognor Regis},
      publisher    = {Wiley-Liss},
      reportid     = {DKFZ-2019-02849},
      pages        = {1059-1070},
      year         = {2020},
      note         = {2020 Aug 15;147(4):1059-1070},
      abstract     = {Progress in the systemic control of osteosarcoma has been
                      limited over the past decades thus indicating the urgent
                      clinical need for the development of novel treatment
                      strategies. Therefore, we have recently developed new
                      preclinical models to study promising novel agents for the
                      treatment of pediatric osteosarcoma. The checkpoint kinase
                      (chk) inhibitor prexasertib (LY2606368) and its salt form
                      (LSN2940930) have recently been shown to be active in adult
                      and pediatric malignancies, including sarcoma. We have now
                      tested the potency of prexasertib in clonogenic survival
                      assays in two new lines of primary patient-derived
                      osteosarcoma cells and in two established osteosarcoma cell
                      lines as a single agent and in combination with cisplatin
                      and the poly ADP-ribose polymerase (PARP) inhibitor
                      talazoparib. Prexasertib alone results in strongly reduced
                      clonogenic survival at low nanomolar concentrations and acts
                      by affecting cell cycle progression, induction of apoptosis
                      and induction of double-stranded DNA breakage at
                      concentrations that are well below clinically tolerable and
                      safe plasma concentrations. In combination with cisplatin
                      and talazoparib, prexasertib acts in a synergistic fashion.
                      Chk1 inhibition by prexasertib and its combination with the
                      DNA damaging agent cisplatin and the PARP-inhibitor
                      talazoparib thus emerges as a potential new treatment option
                      for pediatric osteosarcoma which will now have to be tested
                      in preclinical primary patient derived in vivo models and
                      clinical studies. This article is protected by copyright.
                      All rights reserved.},
      cin          = {E055 / HD01},
      ddc          = {610},
      cid          = {I:(DE-He78)E055-20160331 / I:(DE-He78)HD01-20160331},
      pnm          = {315 - Imaging and radiooncology (POF3-315)},
      pid          = {G:(DE-HGF)POF3-315},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:31782150},
      doi          = {10.1002/ijc.32814},
      url          = {https://inrepo02.dkfz.de/record/148283},
}