BRAFΔβ3-αC in-frame deletion mutants differ in their dimerization propensity, HSP90 dependence, and druggability

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Manuel Lauinger - , University of Freiburg (Author)
  • Daniel Christen - , University of Freiburg (Author)
  • Rhena F U Klar - , University of Freiburg (Author)
  • Carole Roubaty - , University of Fribourg (Author)
  • Christoph E Heilig - , National Center for Tumor Diseases (NCT) Heidelberg, German Cancer Research Center (DKFZ) (Author)
  • Michael Stumpe - , University of Fribourg (Author)
  • Jennifer J Knox - , Ontario Institute for Cancer Research (Author)
  • Nikolina Radulovich - , University Health Network (UHN) (Author)
  • Laura Tamblyn - , University Health Network (UHN) (Author)
  • Irene Y Xie - , University Health Network (UHN) (Author)
  • Peter Horak - , National Center for Tumor Diseases (NCT) Heidelberg, German Cancer Research Center (DKFZ) (Author)
  • Andrea Forschner - , University Hospital Tübingen (Author)
  • Michael Bitzer - , University of Tübingen (Author)
  • Uwe A Wittel - , University Medical Center Freiburg (Author)
  • Melanie Boerries - , German Cancer Consortium (DKTK) partner site Freiburg (Author)
  • Claudia R Ball - , National Center for Tumor Diseases (Partners: UKD, MFD, HZDR, DKFZ), German Cancer Consortium (DKTK) Partner Site Dresden, German Cancer Research Center (DKFZ), University Hospital Carl Gustav Carus Dresden (Author)
  • Christoph Heining - , National Center for Tumor Diseases (Partners: UKD, MFD, HZDR, DKFZ), German Cancer Consortium (DKTK) Partner Site Dresden, German Cancer Research Center (DKFZ), University Hospital Carl Gustav Carus Dresden (Author)
  • Hanno Glimm - , National Center for Tumor Diseases (Partners: UKD, MFD, HZDR, DKFZ), German Cancer Consortium (DKTK) Partner Site Dresden, German Cancer Research Center (DKFZ), University Hospital Carl Gustav Carus Dresden (Author)
  • Martina Fröhlich - , National Center for Tumor Diseases (NCT) Heidelberg (Author)
  • Daniel Hübschmann - , German Cancer Consortium (DKTK) Partner Site Dresden (Author)
  • Steven Gallinger - , Ontario Institute for Cancer Research (Author)
  • Ralph Fritsch - , University Medical Center Freiburg (Author)
  • Stefan Fröhling - , National Center for Tumor Diseases (NCT) Heidelberg (Author)
  • Grainne M O'Kane - , Ontario Institute for Cancer Research (Author)
  • Jörn Dengjel - , University of Fribourg (Author)
  • Tilman Brummer - , University of Freiburg (Author)

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.

Details

Original languageEnglish
Article numbereade7486
Pages (from-to)eade7486
JournalScience advances
Volume9
Issue number35
Publication statusPublished - Sept 2023
Peer-reviewedYes

External IDs

Scopus 85169521320

Keywords

Keywords

  • Humans, Dimerization, Proto-Oncogene Proteins B-raf/genetics, HSP90 Heat-Shock Proteins, Amino Acids