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@ARTICLE{Cameron:284762,
      author       = {D. P. Cameron and J. Grosser and S. Ladigan and V. Kuzin
                      and E. Iliopoulou and A. Wiegard and H. Benredjem and K.
                      Jackson and S.-T. Liffers$^*$ and S. Lueong$^*$ and P. F.
                      Cheung$^*$ and D. Vangala and M. Pohl and R. Viebahn and C.
                      Teschendorf and H. Wolters and S. Usta and K. Geng and C.
                      Kutter and M. Arsenian-Henriksson and J. Siveke$^*$ and A.
                      Tannapfel and W. Schmiegel and S. A. Hahn and L. Baranello},
      title        = {{C}oinhibition of topoisomerase 1 and {BRD}4-mediated pause
                      release selectively kills pancreatic cancer via readthrough
                      transcription.},
      journal      = {Science advances},
      volume       = {9},
      number       = {41},
      issn         = {2375-2548},
      address      = {Washington, DC [u.a.]},
      publisher    = {Assoc.},
      reportid     = {DKFZ-2023-02073},
      pages        = {eadg5109},
      year         = {2023},
      abstract     = {Pancreatic carcinoma lacks effective therapeutic strategies
                      resulting in poor prognosis. Transcriptional dysregulation
                      due to alterations in KRAS and MYC affects initiation,
                      development, and survival of this tumor type. Using
                      patient-derived xenografts of KRAS- and MYC-driven
                      pancreatic carcinoma, we show that coinhibition of
                      topoisomerase 1 (TOP1) and bromodomain-containing protein 4
                      (BRD4) synergistically induces tumor regression by targeting
                      promoter pause release. Comparing the nascent transcriptome
                      with the recruitment of elongation and termination factors,
                      we found that coinhibition of TOP1 and BRD4 disrupts
                      recruitment of transcription termination factors. Thus, RNA
                      polymerases transcribe downstream of genes for hundreds of
                      kilobases leading to readthrough transcription. This occurs
                      during replication, perturbing replisome progression and
                      inducing DNA damage. The synergistic effect of TOP1 + BRD4
                      inhibition is specific to cancer cells leaving normal cells
                      unaffected, highlighting the tumor's vulnerability to
                      transcriptional defects. This preclinical study provides a
                      mechanistic understanding of the benefit of combining TOP1
                      and BRD4 inhibitors to treat pancreatic carcinomas addicted
                      to oncogenic drivers of transcription and replication.},
      cin          = {ED01},
      ddc          = {500},
      cid          = {I:(DE-He78)ED01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:37831776},
      pmc          = {pmc:PMC10575591},
      doi          = {10.1126/sciadv.adg5109},
      url          = {https://inrepo02.dkfz.de/record/284762},
}