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@ARTICLE{Kapp:302049,
      author       = {J. N. Kapp and W. P. R. Verdurmen and J. V. Schaefer and K.
                      Kopra and G. Nagy-Davidescu and E. Richard and M.-J. Nokin
                      and P. Ernst and R. Tamaskovic and M. Schwill and R. Degen
                      and C. Scholl$^*$ and D. Santamaria and A. Plückthun},
      title        = {{A} nucleotide-independent, pan-{RAS}-targeted {DARP}in
                      elicits anti-tumor activity in a multimodal manner.},
      journal      = {Molecular oncology},
      volume       = {nn},
      issn         = {1574-7891},
      address      = {Hoboken, NJ},
      publisher    = {John Wiley $\&$ Sons, Inc.},
      reportid     = {DKFZ-2025-01240},
      pages        = {nn},
      year         = {2025},
      note         = {epub},
      abstract     = {The KRAS oncoprotein is a frequent tumor driver in lung,
                      pancreatic, and colorectal cancers and has proven to be a
                      challenging pharmaceutical target. The first KRAS-targeted
                      therapeutics are now being tested in clinical trials but the
                      consequences of preferentially targeting the GDP or GTP
                      state of KRAS and the relevance of RAS nanoclustering have
                      remained unclear. Here we report a Designed Ankyrin Repeat
                      Protein (DARPin) that recognizes the RAS switch I/II region
                      with low nm affinity, independently of the nucleotide bound
                      (GDP- or GTP state). This DARPin, termed $'784_F5',$
                      occupies the effector recognition lobe, resulting in
                      interference with SOS-mediated activation, RAS downstream
                      effector interactions, and KRAS nanoclustering.
                      Consequently, this anti-RAS DARPin potently blocks
                      downstream signaling, leading to a strong reduction in
                      proliferation and anchorage-independent growth in
                      RAS-dependent cell lines. We showed that the expression of
                      $'784_F5',$ the pan-RAS, nucleotide-independent DARPin can
                      lead to tumor regression in a colorectal xenograft model
                      which may hold promise for further investigation and
                      development.},
      keywords     = {Designed Ankyrin Repeat Protein (Other) / RAS (Other) /
                      cancer (Other) / drug development (Other) / oncogene (Other)
                      / small GTPase (Other)},
      cin          = {B290},
      ddc          = {610},
      cid          = {I:(DE-He78)B290-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40517320},
      doi          = {DOI:10.1002/1878-0261.70061},
      url          = {https://inrepo02.dkfz.de/record/302049},
}