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@ARTICLE{Klotz:278410,
      author       = {D. M. Klotz$^*$ and F. M. Schwarz$^*$ and A. Dubrovska$^*$
                      and K. Schuster$^*$ and M. Theis and A. Krüger$^*$ and O.
                      Kutz$^*$ and T. Link$^*$ and P. Wimberger$^*$ and S.
                      Drukewitz$^*$ and F. Buchholz$^*$ and J. Thomale and J. D.
                      Kuhlmann$^*$},
      title        = {{E}stablishment and {M}olecular {C}haracterization of an
                      {I}n {V}itro {M}odel for {PARP}i-{R}esistant {O}varian
                      {C}ancer.},
      journal      = {Cancers},
      volume       = {15},
      number       = {15},
      issn         = {2072-6694},
      address      = {Basel},
      publisher    = {MDPI},
      reportid     = {DKFZ-2023-01644},
      pages        = {3774},
      year         = {2023},
      abstract     = {Overcoming PARPi resistance is a high clinical priority. We
                      established and characterized comparative in vitro models of
                      acquired PARPi resistance, derived from either a
                      BRCA1-proficient or BRCA1-deficient isogenic background by
                      long-term exposure to olaparib. While parental cell lines
                      already exhibited a certain level of intrinsic activity of
                      multidrug resistance (MDR) proteins, resulting
                      PARPi-resistant cells from both models further converted
                      toward MDR. In both models, the PARPi-resistant phenotype
                      was shaped by (i) cross-resistance to other PARPis (ii)
                      impaired susceptibility toward the formation of DNA-platinum
                      adducts upon exposure to cisplatin, which could be reverted
                      by the drug efflux inhibitors verapamil or diphenhydramine,
                      and (iii) reduced PARP-trapping activity. However, the
                      signature and activity of ABC-transporter expression and the
                      cross-resistance spectra to other chemotherapeutic drugs
                      considerably diverged between the BRCA1-proficient vs.
                      BRCA1-deficient models. Using dual-fluorescence co-culture
                      experiments, we observed that PARPi-resistant cells had a
                      competitive disadvantage over PARPi-sensitive cells in a
                      drug-free medium. However, they rapidly gained clonal
                      dominance under olaparib selection pressure, which could be
                      mitigated by the MRP1 inhibitor MK-751. Conclusively, we
                      present a well-characterized in vitro model, which could be
                      instrumental in dissecting mechanisms of PARPi resistance
                      from HR-proficient vs. HR-deficient background and in
                      studying clonal dynamics of PARPi-resistant cells in
                      response to experimental drugs, such as novel
                      olaparib-sensitizers.},
      keywords     = {PARPi resistance (Other) / cisplatin (Other) / ovarian
                      cancer (Other)},
      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:37568590},
      pmc          = {pmc:PMC10417418},
      doi          = {10.3390/cancers15153774},
      url          = {https://inrepo02.dkfz.de/record/278410},
}