BRAFΔβ3-αC in-frame deletion mutants differ in their dimerization propensity, HSP90 dependence, and druggability
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...
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| Hauptverfasser: | , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
2023
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| In: |
Science advances
Year: 2023, Jahrgang: 9, Heft: 35, Pages: 1-22 |
| ISSN: | 2375-2548 |
| DOI: | 10.1126/sciadv.ade7486 |
| Online-Zugang: | Verlag, kostenfrei, Volltext: https://doi.org/10.1126/sciadv.ade7486 Verlag, kostenfrei, Volltext: https://www.science.org/doi/10.1126/sciadv.ade7486 
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| Verfasserangaben: | Manuel Lauinger, Daniel Christen, Rhena F. U. Klar, Carole Roubaty, Christoph E. Heilig, Michael Stumpe, Jennifer J. Knox, Nikolina Radulovich, Laura Tamblyn, Irene Y. Xie, Peter Horak, Andrea Forschner, Michael Bitzer, Uwe A. Wittel, Melanie Boerries, Claudia R. Ball, Christoph Heining, Hanno Glimm, Martina Fröhlich, Daniel Hübschmann, Steven Gallinger, Ralph Fritsch, Stefan Fröhling, Grainne M. O’Kane, Jörn Dengjel, Tilman Brummer |
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| 245 | 1 | 0 | |a BRAFΔβ3-αC in-frame deletion mutants differ in their dimerization propensity, HSP90 dependence, and druggability |c Manuel Lauinger, Daniel Christen, Rhena F. U. Klar, Carole Roubaty, Christoph E. Heilig, Michael Stumpe, Jennifer J. Knox, Nikolina Radulovich, Laura Tamblyn, Irene Y. Xie, Peter Horak, Andrea Forschner, Michael Bitzer, Uwe A. Wittel, Melanie Boerries, Claudia R. Ball, Christoph Heining, Hanno Glimm, Martina Fröhlich, Daniel Hübschmann, Steven Gallinger, Ralph Fritsch, Stefan Fröhling, Grainne M. O’Kane, Jörn Dengjel, Tilman Brummer |
| 246 | 3 | 3 | |a BRAF Delta beta 3-alpha C in-frame deletion mutants differ in their dimerization propensity, HSP90 dependence, and druggability |
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| 520 | |a 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. | ||
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