Molecular Modeling Unveils the Effective Interaction of B-RAF Inhibitors with Rare B-RAF Insertion Variants

The Food and Drug Administration (FDA) has approved MAPK inhibitors as a treatment for melanoma patients carrying a mutation in codon V600 of the BRAF gene exclusively. However, BRAF mutations outside the V600 codon may occur in a small percentage of melanomas. Although these rare variants may cause B-RAF activation, their predictive response to B-RAF inhibitor treatments is still poorly understood. We exploited an integrated approach for mutation detection, tumor evolution tracking, and assessment of response to treatment in a metastatic melanoma patient carrying the rare p.T599dup B-RAF mutation. He was addressed to Dabrafenib/Trametinib targeted therapy, showing an initial dramatic response. In parallel, in-silico ligand-based homology modeling was set up and performed on this and an additional B-RAF rare variant (p.A598_T599insV) to unveil and justify the success of the B-RAF inhibitory activity of Dabrafenib, showing that it could adeptly bind both these variants in a similar manner to how it binds and inhibits the V600E mutant. These findings open up the possibility of broadening the spectrum of BRAF inhibitor-sensitive mutations beyond mutations at codon V600, suggesting that B-RAF V600 WT melanomas should undergo more specific investigations before ruling out the possibility of targeted therapy.

Automated summary

The FDA has approved MAPK inhibitors for treating melanoma patients with BRAF gene mutation in the V600 codon. However, rare BRAF mutations outside the V600 codon may also cause melanoma, and their response to BRAF inhibitor treatment is still not well understood. In this study, a patient with a rare p.T599dup B-RAF mutation was found to have a good response to Dabrafenib/Trametinib targeted therapy. In-silico modeling showed that Dabrafenib could effectively bind to this rare mutation, suggesting the possibility of broadening the spectrum of BRAF inhibitor-sensitive mutations beyond the V600 codon.