> Details
Lauinger, Manuel
[Author];
Christen, Daniel
[Author];
Klar, Rhena F. U
[Author];
Roubaty, Carole
[Author];
Heilig, Christoph E.
[Author];
Stumpe, Michael
[Author];
Knox, Jennifer J.
[Author];
Radulovich, Nikolina
[Author];
Tamblyn, Laura
[Author];
Xie, Irene Y.
[Author];
Horak, Peter
[Author];
Forschner, Andrea
[Author];
Bitzer, Michael
[Author];
Wittel, Uwe A.
[Author];
Boerries, Melanie
[Author];
Ball, Claudia R.
[Author];
Heining, Christoph
[Author];
Glimm, Hanno
[Author];
Fröhlich, Martina
[Author];
Hübschmann, Daniel
[Author];
Gallinger, Steven
[Author];
Fritsch, Ralph
[Author];
Fröhling, Stefan
[Author];
O’Kane, Grainne M.
[Author];
[...]
BRAFΔβ3-αC in-frame deletion mutants differ in their dimerization propensity, HSP90 dependence, and druggability
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- Media type: E-Article
- Title: BRAFΔβ3-αC in-frame deletion mutants differ in their dimerization propensity, HSP90 dependence, and druggability
- Contributor: Lauinger, Manuel [VerfasserIn]; Christen, Daniel [VerfasserIn]; Klar, Rhena F. U. [VerfasserIn]; Roubaty, Carole [VerfasserIn]; Heilig, Christoph E. [VerfasserIn]; Stumpe, Michael [VerfasserIn]; Knox, Jennifer J. [VerfasserIn]; Radulovich, Nikolina [VerfasserIn]; Tamblyn, Laura [VerfasserIn]; Xie, Irene Y. [VerfasserIn]; Horak, Peter [VerfasserIn]; Forschner, Andrea [VerfasserIn]; Bitzer, Michael [VerfasserIn]; Wittel, Uwe A. [VerfasserIn]; Boerries, Melanie [VerfasserIn]; Ball, Claudia R. [VerfasserIn]; Heining, Christoph [VerfasserIn]; Glimm, Hanno [VerfasserIn]; Fröhlich, Martina [VerfasserIn]; Hübschmann, Daniel [VerfasserIn]; Gallinger, Steven [VerfasserIn]; Fritsch, Ralph [VerfasserIn]; Fröhling, Stefan [VerfasserIn]; O’Kane, Grainne M. [VerfasserIn]; Dengjel, Jörn [VerfasserIn]; Brummer, Tilman [VerfasserIn]
-
imprint:
2023
- Published in: Science advances ; 9(2023), 35, Artikel-ID eade7486, Seite 1-22
- Language: English
- DOI: 10.1126/sciadv.ade7486
- ISSN: 2375-2548
- Identifier:
- Origination:
-
Footnote:
Veröffentlicht: 1. September 2023
Der Ausdruck "Δβ3-αC" ist im Titel hochgestellt
- Description: 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.
- Access State: Open Access