BRAFΔß3-αC in-frame deletion mutants differ in their dimerization propensity, HSP90 dependence, and druggability.
Sci Adv
; 9(35): eade7486, 2023 09.
Article
in En
| MEDLINE
| ID: mdl-37656784
ABSTRACT
In-frame BRAF exon 12 deletions are increasingly identified in various tumor types. The resultant BRAFΔß3-αC oncoproteins usually lack five amino acids in the ß3-αC helix linker and sometimes contain de novo insertions. The dimerization status of BRAFΔß3-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 BRAFΔß3-αC oncoproteins. We show that BRAFΔß3-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 BRAFΔß3-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 BRAFΔß3-αC mutants in cell lines and patient-derived organoids, suggesting that tumors driven by such oncoproteins are vulnerable to these compounds.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
HSP90 Heat-Shock Proteins
/
Proto-Oncogene Proteins B-raf
Limits:
Humans
Language:
En
Journal:
Sci Adv
Year:
2023
Document type:
Article