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@ARTICLE{Schwarz:298596,
      author       = {F. M. Schwarz$^*$ and D. M. Klotz$^*$ and R. Yang$^*$ and
                      M. Brux and F. Buchholz$^*$ and H. Harb and T. Link$^*$ and
                      P. Wimberger$^*$ and M. Theis and J. D. Kuhlmann$^*$},
      title        = {{M}ethylstat sensitizes ovarian cancer cells to
                      {PARP}-inhibition by targeting the histone demethylases
                      {JMJD}1{B}/{C}.},
      journal      = {Cancer gene therapy},
      volume       = {32},
      number       = {3},
      issn         = {0929-1903},
      address      = {New York, NY},
      publisher    = {Nature Publ. Group},
      reportid     = {DKFZ-2025-00306},
      pages        = {286-296},
      year         = {2025},
      note         = {2025 Mar;32(3):286-296},
      abstract     = {PARP-inhibitors (PARPi) are an integral part of ovarian
                      cancer treatment. However, overcoming acquired PARPi
                      resistance or increasing the benefit of PARPi in patients
                      without homologous recombination deficiency (HRD) remains an
                      unmet clinical need. We sought to identify genetic
                      modulators of PARPi response, guiding pharmacological PARPi
                      sensitization. CRISPR-Cas9 mediated loss-of-function screen
                      with a focused sgRNA library revealed that DNA-demethylases
                      JMJD1B/JMJD1C, targetable by the small inhibitor methylstat,
                      promote PARPi resistance. Methylstat synergistically
                      interacted with olaparib, and (re-)sensitized ovarian cancer
                      cells to PARPi treatment, surpassing the efficacy of common
                      demethylase inhibitors. Genetic knockout of JMJD1B and/or
                      JMJD1C phenocopied the effect of methylstat in an additive
                      manner. Validation studies revealed methylstat to be a
                      universal PARPi-sensitizing drug, effective, regardless of
                      PARPi resistance status or BRCA1 mutational background.
                      Methylstat modulated clonal cancer dynamics by mitigating
                      positive selection of PARPi-resistant or BRCA1-proficient
                      cells under olaparib treatment. Using a model of
                      PARPi-induced cellular toxicity, we showed that methylstat
                      impairs cellular DNA repair, indicated by an increased
                      susceptibility of ovarian cancer cells to olaparib-induced
                      DNA double strand breaks after methylstat exposure. This
                      study proposes the histone demethylase inhibitor methylstat
                      as an epigenetic drug for overcoming PARPi-resistance or for
                      increasing efficacy of PARPi beyond HRD in ovarian cancer
                      patients.},
      cin          = {DD01},
      ddc          = {610},
      cid          = {I:(DE-He78)DD01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:39915607},
      doi          = {10.1038/s41417-025-00874-z},
      url          = {https://inrepo02.dkfz.de/record/298596},
}