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@ARTICLE{Zhao:300286,
      author       = {B. Zhao$^*$ and R. Fang$^*$ and H. Schürmann$^*$ and E. J.
                      Hemmer$^*$ and G. L. Mayer$^*$ and M. Trajkovic-Arsic$^*$
                      and K. Althoff$^*$ and J. Yang$^*$ and L. Godfrey$^*$ and S.
                      T. Liffers$^*$ and K. Savvatakis$^*$ and M. Dorsch$^*$ and
                      B. M. Grüner$^*$ and S. Hahn and M. Remke$^*$ and S. S.
                      Lueong$^*$ and J. T. Siveke$^*$},
      title        = {{PLK}1 blockade enhances the anti-tumor effect of {MAPK}
                      inhibition in pancreatic ductal adenocarcinoma.},
      journal      = {Cell reports},
      volume       = {44},
      number       = {4},
      issn         = {2211-1247},
      address      = {Maryland Heights, MO},
      publisher    = {Cell Press},
      reportid     = {DKFZ-2025-00739},
      pages        = {115541},
      year         = {2025},
      abstract     = {Despite constitutive Ras/Raf/MAPK pathway activation in
                      most pancreatic ductal adenocarcinomas (PDACs), treatment
                      approaches targeting this pathway have primarily been
                      unsuccessful. We conduct a drug library screen on an MEK
                      inhibitor (MEKi)-resistant PDAC model and perform
                      complementary pathway analysis to identify cellular
                      resistance phenotypes. We use syngeneic models to
                      investigate the molecular determinants of identified drug
                      synergism. Our study reveals an enrichment for the hallmarks
                      of G2/M checkpoints in MEKi-resistant phenotypes from all
                      investigated models. We find overexpression of Polo-like
                      kinase 1 (PLK1) and other G2/M checkpoint-related proteins
                      in MEKi-resistant cells. We identify synergistic activity
                      between MEK and PLK1 inhibition both in vitro and in vivo
                      and mechanistically show that dual inhibition of the PLK1
                      and MEK pathways activates the JNK/c-JUN pathway. This
                      causes the accumulation of DNA damage, ultimately leading to
                      apoptotic cell death. Dual PLK1/MEK inhibition emerges as a
                      promising targeted approach in PDAC.},
      keywords     = {CP: Cancer (Other) / G1 arrest (Other) / G2/M checkpoint
                      (Other) / JNK (Other) / KRAS (Other) / MAPK (Other) / MEK
                      (Other) / PDAC (Other) / PDO (Other) / PLK1 (Other) / cJUN
                      (Other) / cell cycle (Other) / organoids (Other) / synergism
                      (Other) / therapy resistance (Other) / trametinib (Other) /
                      volasertib (Other)},
      cin          = {ED01},
      ddc          = {610},
      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:40188436},
      doi          = {10.1016/j.celrep.2025.115541},
      url          = {https://inrepo02.dkfz.de/record/300286},
}