Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• International journal of molecular sciences, 2023-08, Vol.24 (15), p.12285

Ort / Verlag

Switzerland: MDPI AG

Erscheinungsjahr

2023

Link zum Volltext

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• 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.