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@ARTICLE{Lauinger:282502,
      author       = {M. Lauinger and D. Christen$^*$ and R. Klar$^*$ and C.
                      Roubaty and C. Heilig$^*$ and M. Stumpe and J. J. Knox and
                      N. Radulovich and L. Tamblyn and I. Y. Xie and P. Horak$^*$
                      and A. Forschner$^*$ and M. Bitzer$^*$ and U. A. Wittel and
                      M. Börries$^*$ and C. Ball$^*$ and C. Heining$^*$ and H.
                      Glimm$^*$ and M. Fröhlich and D. Hübschmann$^*$ and S.
                      Gallinger and R. Fritsch and S. Fröhling$^*$ and G. M.
                      O'Kane and J. Dengjel and T. Brummer$^*$},
      title        = {{BRAF}Δβ3-α{C} in-frame deletion mutants differ in their
                      dimerization propensity, {HSP}90 dependence, and
                      druggability.},
      journal      = {Science advances},
      volume       = {9},
      number       = {35},
      issn         = {2375-2548},
      address      = {Washington, DC [u.a.]},
      publisher    = {Assoc.},
      reportid     = {DKFZ-2023-01791},
      pages        = {eade7486},
      year         = {2023},
      abstract     = {In-frame BRAF exon 12 deletions are increasingly identified
                      in various tumor types. The resultant BRAFΔβ3-αC
                      oncoproteins usually lack five amino acids in the β3-αC
                      helix linker and sometimes contain de novo insertions. The
                      dimerization status of BRAFΔβ3-αC oncoproteins, their
                      precise pathomechanism, and their direct druggability by RAF
                      inhibitors (RAFi) has been under debate. Here, we
                      functionally characterize BRAFΔLNVTAP>F and two novel
                      mutants, BRAFdelinsFS and BRAFΔLNVT>F, and compare them
                      with other BRAFΔβ3-αC oncoproteins. We show that
                      BRAFΔβ3-αC oncoproteins not only form stable homodimers
                      and large multiprotein complexes but also require
                      dimerization. Nevertheless, details matter as aromatic amino
                      acids at the deletion junction of some BRAFΔβ3-αC
                      oncoproteins, e.g., BRAFΔLNVTAP>F, increase their stability
                      and dimerization propensity while conferring resistance to
                      monomer-favoring RAFi such as dabrafenib or HSP 90/CDC37
                      inhibition. In contrast, dimer-favoring inhibitors such as
                      naporafenib inhibit all BRAFΔβ3-αC mutants in cell lines
                      and patient-derived organoids, suggesting that tumors driven
                      by such oncoproteins are vulnerable to these compounds.},
      cin          = {FR01 / B340 / HD01 / TU01 / DD01},
      ddc          = {500},
      cid          = {I:(DE-He78)FR01-20160331 / I:(DE-He78)B340-20160331 /
                      I:(DE-He78)HD01-20160331 / I:(DE-He78)TU01-20160331 /
                      I:(DE-He78)DD01-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:37656784},
      doi          = {10.1126/sciadv.ade7486},
      url          = {https://inrepo02.dkfz.de/record/282502},
}