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

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...

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Bibliographic Details
Main Authors: Maria Chiara Scaini, Luisa Piccin, Davide Bassani, Antonio Scapinello, Stefania Pellegrini, Cristina Poggiana, Cristina Catoni, Debora Tonello, Jacopo Pigozzo, Luigi Dall’Olmo, Antonio Rosato, Stefano Moro, Vanna Chiarion-Sileni, Chiara Menin
Format: Article
Language:English
Published: MDPI AG 2023-07-01
Series:International Journal of Molecular Sciences
Subjects:
ligand-based homology modeling
molecular docking calculation
BRAF rare mutations
advanced melanoma
targeted therapy
liquid biopsy
Online Access:https://www.mdpi.com/1422-0067/24/15/12285
Description
Summary: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.
ISSN:1661-6596
1422-0067

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