% IMPORTANT: The following is UTF-8 encoded.  This means that in the presence
% of non-ASCII characters, it will not work with BibTeX 0.99 or older.
% Instead, you should use an up-to-date BibTeX implementation like “bibtex8” or
% “biber”.

@ARTICLE{Aust:303097,
      author       = {O. Aust and M. R. T. Thiel and E. Blanc and M. Lüthen and
                      V. Hollek and R. Astaburuaga-García and B. Klinger and F.
                      Böhning and A. Trinks and D. Beule and B. Papke$^*$ and D.
                      Horst$^*$ and N. Blüthgen$^*$ and C. Sers$^*$ and C. J. Der
                      and M. Morkel$^*$},
      title        = {{R}eporter-based screening identifies {RAS}-{RAF} mutations
                      as drivers of resistance to active-state {RAS} inhibitors in
                      colorectal cancer.},
      journal      = {Science signaling},
      volume       = {18},
      number       = {896},
      issn         = {1945-0877},
      address      = {Washington, DC [u.a.]},
      publisher    = {Assoc.},
      reportid     = {DKFZ-2025-01522},
      pages        = {eadr3738},
      year         = {2025},
      abstract     = {Therapy-induced acquired resistance limits the clinical
                      effectiveness of mutation-specific KRAS inhibitors in
                      colorectal cancer (CRC). Here, we investigated whether
                      broad-spectrum, active-state RAS inhibitors meet similar
                      limitations. We found that KRAS-mutant CRC cell lines were
                      sensitive to the RAS(ON) multiselective RAS inhibitor
                      RMC-7977, given that treatment resulted in RAS-RAF-MEK-ERK
                      pathway inhibition; halted proliferation; and, in some
                      cases, induced apoptosis. RMC-7977 initially reduced the
                      activity of a compartment-specific, dual-color reporter of
                      ERK activity, with reporter reactivation emerging after
                      long-term dose escalation. These drug-resistant cell
                      populations exhibited distinct patterns of phospho-protein
                      abundance, transcriptional activities, and genomic
                      mutations, including a Y71H mutation in KRAS and an S257L
                      mutation in RAF1. Transgenic expression of KRASG13D, Y71H or
                      RAF1S257L in drug-sensitive CRC cells induced resistance to
                      RMC-7977. CRC cells that were resistant to RMC-7977 and
                      harboring RAF1S257L exhibited synergistic sensitivity to
                      concurrent inhibition of RAS and RAF. Our findings
                      demonstrate the power of reporter-assisted screening
                      together with single-cell analyses for dissecting the
                      complex landscape of therapy resistance. The strategy offers
                      opportunities to develop clinically relevant combinatorial
                      treatments to counteract the emergence of resistant cancer
                      cells.},
      keywords     = {Humans / Colorectal Neoplasms: genetics / Colorectal
                      Neoplasms: drug therapy / Colorectal Neoplasms: pathology /
                      Colorectal Neoplasms: metabolism / Drug Resistance,
                      Neoplasm: genetics / Drug Resistance, Neoplasm: drug effects
                      / Proto-Oncogene Proteins c-raf: genetics / Proto-Oncogene
                      Proteins c-raf: metabolism / Proto-Oncogene Proteins
                      p21(ras): genetics / Proto-Oncogene Proteins p21(ras):
                      antagonists $\&$ inhibitors / Proto-Oncogene Proteins
                      p21(ras): metabolism / Cell Line, Tumor / Mutation / Genes,
                      Reporter / MAP Kinase Signaling System: drug effects / MAP
                      Kinase Signaling System: genetics / Apoptosis: drug effects
                      / Proto-Oncogene Proteins c-raf (NLM Chemicals) /
                      Proto-Oncogene Proteins p21(ras) (NLM Chemicals) / KRAS
                      protein, human (NLM Chemicals) / Raf1 protein, human (NLM
                      Chemicals)},
      cin          = {BE01},
      ddc          = {500},
      cid          = {I:(DE-He78)BE01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40694611},
      doi          = {10.1126/scisignal.adr3738},
      url          = {https://inrepo02.dkfz.de/record/303097},
}