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

Area of Science:

• Oncology
• Molecular Biology
• Cancer Genetics

Background:

• In-frame BRAF exon 12 deletions are emerging in various cancers, producing BRAFΔβ3-αC oncoproteins.
• The exact dimerization, pathomechanism, and druggability of BRAFΔβ3-αC oncoproteins by RAF inhibitors (RAFi) remain debated.

Purpose of the Study:

• To functionally characterize novel BRAFΔβ3-αC mutants (BRAFΔLNVTAP>F, BRAFdelinsFS, BRAFΔLNVT>F).
• To compare these mutants with existing BRAFΔβ3-αC oncoproteins.
• To investigate the role of dimerization in BRAFΔβ3-αC oncoprotein activity and drug sensitivity.

Main Methods:

• Functional characterization of BRAF mutants in cell lines.
• Assessment of protein complex formation and dimerization status.
• Evaluation of sensitivity to RAF inhibitors (RAFi) and HSP 90/CDC37 inhibition.

Main Results:

• BRAFΔβ3-αC oncoproteins form stable homodimers and large complexes, requiring dimerization for activity.
• Aromatic amino acids at the deletion junction enhance stability and dimerization, conferring resistance to monomer-favoring RAFi like dabrafenib.
• Dimer-favoring inhibitors, such as naporafenib, effectively inhibit all tested BRAFΔβ3-αC mutants.

Conclusions:

• BRAFΔβ3-αC oncoproteins are obligate dimers.
• Tumors driven by BRAFΔβ3-αC oncoproteins are sensitive to dimer-favoring RAF inhibitors.
• Targeting BRAF dimerization offers a promising therapeutic avenue for cancers with these mutations.