Details

Autor(en) / Beteiligte

• Lauinger, Manuel
• Christen, Daniel
• Klar, Rhena F. U.
• Roubaty, Carole
• Heilig, Christoph E.
• Stumpe, Michael
• Knox, Jennifer J.
• Radulovich, Nikolina
• Tamblyn, Laura
• Xie, Irene Y.
• Horak, Peter
• Forschner, Andrea
• Bitzer, Michael
• Wittel, Uwe A.
• Boerries, Melanie
• Ball, Claudia R.
• Heining, Christoph
• Glimm, Hanno
• Fröhlich, Martina
• Hübschmann, Daniel
• Gallinger, Steven
• Fritsch, Ralph
• Fröhling, Stefan
• O’Kane, Grainne M.
• Dengjel, Jörn
• Brummer, Tilman

Titel

BRAF Δβ3-αC in-frame deletion mutants differ in their dimerization propensity, HSP90 dependence, and druggability

Ist Teil von

• Science advances, 2023-09, Vol.9 (35), p.eade7486-eade7486

Erscheinungsjahr

2023

Quelle

EZB Free E-Journals

Beschreibungen/Notizen

• In-frame BRAF exon 12 deletions are increasingly identified in various tumor types. The resultant BRAF Δβ3-αC oncoproteins usually lack five amino acids in the β3-αC helix linker and sometimes contain de novo insertions. The dimerization status of BRAF Δβ3-αC oncoproteins, their precise pathomechanism, and their direct druggability by RAF inhibitors (RAFi) has been under debate. Here, we functionally characterize BRAF ΔLNVTAP>F and two novel mutants, BRAF delinsFS and BRAF ΔLNVT>F , and compare them with other BRAF Δβ3-αC oncoproteins. We show that BRAF Δβ3-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 BRAF Δβ3-αC oncoproteins, e.g., BRAF ΔLNVTAP>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 BRAF Δβ3-αC mutants in cell lines and patient-derived organoids, suggesting that tumors driven by such oncoproteins are vulnerable to these compounds. Aromatic amino acid insertions define the properties of BRAF3-C mutants.