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@ARTICLE{White:306549,
      author       = {M. White and M. L. Mills and L. M. Millett and K. Gilroy
                      and Y. Hong and L. B. Zeiger and R. J. Simpson and S. M.
                      Corry and A. Ligeza and T. R. M. Lannagan and S. Susanti and
                      R. A. Ridgway and A. S. Yazgili and L. Grzesiak and R.
                      Amirkhah and C. A. Ford and N. Vlahov and H. Tovell and L.
                      Officer-Jones and C. Ficken and R. Pennie and A. K.
                      Najumudeen and A. Raven and N. Nasreddin and E. Chauhan and
                      A. S. Papanastasiou and C. Nixon and V. Morrison and R.-F.
                      Jackstadt$^*$ and J. S. Graham and C. J. Miller and S. J.
                      Ross and S. T. Barry and V. Pavet and R. H. Wilson and J. Le
                      Quesne and P. D. Dunne and S. Tejpar and S. Leedham and A.
                      D. Campbell and O. J. Sansom},
      title        = {{MAPK}-driven epithelial cell plasticity drives colorectal
                      cancer therapeutic resistance.},
      journal      = {Nature},
      volume       = {650},
      number       = {8102},
      issn         = {0028-0836},
      address      = {London [u.a.]},
      publisher    = {Nature Publ. Group},
      reportid     = {DKFZ-2025-02614},
      pages        = {748-758},
      year         = {2026},
      note         = {2026 Feb;650(8102):748-758},
      abstract     = {The colorectal epithelium is rapidly renewing, with
                      remarkable capacity to regenerate following injury. In
                      colorectal cancer (CRC), this regenerative capacity can be
                      co-opted to drive epithelial plasticity. While oncogenic
                      MAPK signalling in CRC is common, with frequent mutations of
                      both KRAS $(40-50\%)$ and BRAF $(10\%)1,$ inhibition of this
                      pathway typically drives resistance clinically. Given the
                      development of KRAS inhibitors, and licensing of BRAF
                      inhibitor combinations2-4, we have interrogated key
                      mechanisms of resistance to these agents in advanced
                      preclinical CRC models. We show that oncogenic MAPK
                      signalling induces epithelial state changes in vivo, driving
                      adoption of a regenerative/revival stem like population,
                      while inhibition leads to rapid transcriptional remodeling
                      of both Kras- and Braf-mutant tumours, favoring a
                      Wnt-associated, canonical stem phenotype. This drives acute
                      therapeutic resistance in Kras- and delayed resistance in
                      Braf-driven models. Importantly, where plasticity is
                      restrained, such as in early metastatic disease, or through
                      targeting ligand-dependent Wnt-pathway Rnf43 mutations,
                      marked therapeutic responses are observed. This explains the
                      super response to BRAF+EGFR targeted therapies previously
                      observed in a BRAF/RNF43 co-mutant patient population,
                      highlighting the criticality of cellular plasticity in
                      therapeutic response. Together, our data provides clear
                      insight into the mechanisms underpinning resistance to MAPK
                      targeted therapies in CRC. Moreover, strategies that aim to
                      corral stem cell fate, restrict epithelial plasticity or
                      intervene when tumours lack heterogeneity may improve
                      therapeutic efficacy of these agents.},
      cin          = {A013},
      ddc          = {500},
      cid          = {I:(DE-He78)A013-20160331},
      pnm          = {311 - Zellbiologie und Tumorbiologie (POF4-311)},
      pid          = {G:(DE-HGF)POF4-311},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:41286180},
      doi          = {10.1038/s41586-025-09916-w},
      url          = {https://inrepo02.dkfz.de/record/306549},
}