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@ARTICLE{Krausert:179951,
      author       = {S. Krausert$^*$ and S. Brabetz$^*$ and N. L. Mack$^*$ and
                      F. Schmitt-Hoffner$^*$ and B. Schwalm$^*$ and H.
                      Peterziel$^*$ and A. Mangang$^*$ and T. Holland-Letz$^*$ and
                      L. Sieber$^*$ and A. Korshunov$^*$ and I. Oehme$^*$ and N.
                      Jäger$^*$ and O. Witt$^*$ and S. M. Pfister$^*$ and M.
                      Kool$^*$},
      title        = {{P}redictive modeling of resistance to {SMO} inhibition in
                      a patient-derived orthotopic xenograft model of {SHH}
                      medulloblastoma.},
      journal      = {Neuro-oncology advances},
      volume       = {4},
      number       = {1},
      issn         = {2632-2498},
      address      = {Oxford},
      publisher    = {Oxford University Press},
      reportid     = {DKFZ-2022-01000},
      pages        = {vdac026},
      year         = {2022},
      note         = {#EA:B062#LA:B062# / 2022 Mar 13;4(1):vdac026},
      abstract     = {Inhibition of the sonic hedgehog (SHH) pathway with
                      Smoothened (SMO) inhibitors is a promising treatment
                      strategy in SHH-activated medulloblastoma, especially in
                      adult patients. However, the problem is that tumors
                      frequently acquire resistance to the treatment. To
                      understand the underlying resistance mechanisms and to find
                      ways to overcome the resistance, preclinical models that
                      became resistant to SMO inhibition are needed.To induce SMO
                      inhibitor resistant tumors, we have treated a
                      patient-derived xenograft (PDX) model of SHH
                      medulloblastoma, sensitive to SMO inhibition, with 20 mg/kg
                      Sonidegib using an intermitted treatment schedule.
                      Vehicle-treated and resistant models were subjected to
                      whole-genome and RNA sequencing for molecular
                      characterization and target engagement. In vitro drug
                      screens (76 drugs) were performed using Sonidegib-sensitive
                      and -resistant lines to find other drugs to target the
                      resistant lines. One of the top hits was then validated in
                      vivo.Nine independent Sonidegib-resistant PDX lines were
                      generated. Molecular characterization of the resistant
                      models showed that eight models developed missense mutations
                      in SMO and one gained an inactivating point mutation in
                      MEGF8, which acts downstream of SMO as a repressor in the
                      SHH pathway. The in vitro drug screen with
                      Sonidegib-sensitive and -resistant lines identified good
                      efficacy for Selinexor in the resistant line. Indeed, in
                      vivo treatment with Selinexor revealed that it is more
                      effective in resistant than in sensitive models.We report
                      the first human SMO inhibitor resistant medulloblastoma PDX
                      models, which can be used for further preclinical
                      experiments to develop the best strategies to overcome the
                      resistance to SMO inhibitors in patients.},
      keywords     = {SHH Medulloblastoma (Other) / SMO inhibitor (Other) /
                      Selinexor (Other) / Sonidegib (Other) / resistance (Other)},
      cin          = {B062 / HD01 / B310 / C060 / B300},
      ddc          = {610},
      cid          = {I:(DE-He78)B062-20160331 / I:(DE-He78)HD01-20160331 /
                      I:(DE-He78)B310-20160331 / I:(DE-He78)C060-20160331 /
                      I:(DE-He78)B300-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:35475274},
      pmc          = {pmc:PMC9034118},
      doi          = {10.1093/noajnl/vdac026},
      url          = {https://inrepo02.dkfz.de/record/179951},
}