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

Abstract

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.

Characterization of BRAFThr599dup Mutation as a Targetable Driver Mutation Identified in Lung Adenocarcinoma by Comprehensive Genomic Profiling

“…37 A recent report using in silico ligand-based homology modeling demonstrated that dabrafenib could adeptly bind to BRAF Thr599dup in a manner similar to that in which it binds to BRAF V600E . 21 Of note, we also showed that dimerization of BRAF Thr599dup with WT BRAF or WT CRAF was not required to exert oncogenic functions through the genetic knockout of endogenous BRAF or CRAF in Ba/F3 cells. Furthermore, we revealed that mutant-mutant BRAF dimerization was not required for BRAF Thr599dup to signal through introduction of the additional R509H mutation, leading to the lack of intact DIF.…”

“…This mutation has been detected in 2.8% (one of 36) of BRAF-mutant NSCLC, 0.6% (two of 347) of BRAF-mutant thyroid cancer, 3.1% (three of 96) of BRAFmutant nervous system cancer, and 0.24% (eight of 3,119) of all melanomas reported in the AACR GENIE cohort. 6,8,18,19 Although some case reports demonstrated the efficacy of combination BRAF-and MEK-targeted therapies in patients with BRAF Thr599dup -positive cancers, [19][20][21][22] the function and sensitivity of this mutant oncoprotein to targeted therapy are not fully elucidated.…”