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

• Published in: International journal of molecular sciences 2023-07, Vol.24 (15), p.12285
• Main Authors: Scaini, Maria Chiara, Piccin, Luisa, Bassani, Davide, Scapinello, Antonio, Pellegrini, Stefania, Poggiana, Cristina, Catoni, Cristina, Tonello, Debora, Pigozzo, Jacopo, Dall'Olmo, Luigi, Rosato, Antonio, Moro, Stefano, Chiarion-Sileni, Vanna, Menin, Chiara
• Format: Article
• Language: English
• Subjects: Activities of daily living; Algorithms; Antimitotic agents; Antineoplastic agents; Biopsy; Cancer; Care and treatment; Codon; Drug approval; Drug therapy; FDA approval; Gene mutations; Instrument industry; Kinases; Ligands; Melanoma; Metastasis; Mutation; Proteins
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms241512285

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.