TY  - JOUR
AU  - Lauinger, Manuel
AU  - Christen, Daniel
AU  - Klar, Rhena
AU  - Roubaty, Carole
AU  - Heilig, Christoph
AU  - Stumpe, Michael
AU  - Knox, Jennifer J
AU  - Radulovich, Nikolina
AU  - Tamblyn, Laura
AU  - Xie, Irene Y
AU  - Horak, Peter
AU  - Forschner, Andrea
AU  - Bitzer, Michael
AU  - Wittel, Uwe A
AU  - Börries, Melanie
AU  - Ball, Claudia
AU  - Heining, Christoph
AU  - Glimm, Hanno
AU  - Fröhlich, Martina
AU  - Hübschmann, Daniel
AU  - Gallinger, Steven
AU  - Fritsch, Ralph
AU  - Fröhling, Stefan
AU  - O'Kane, Grainne M
AU  - Dengjel, Jörn
AU  - Brummer, Tilman
TI  - BRAFΔβ3-αC in-frame deletion mutants differ in their dimerization propensity, HSP90 dependence, and druggability.
JO  - Science advances
VL  - 9
IS  - 35
SN  - 2375-2548
CY  - Washington, DC [u.a.]
PB  - Assoc.
M1  - DKFZ-2023-01791
SP  - eade7486
PY  - 2023
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:37656784
DO  - DOI:10.1126/sciadv.ade7486
UR  - https://inrepo02.dkfz.de/record/282502
ER  -