Trametinib Induces the Stabilization of a Dual GNAQ p.Gly48Leu- and FGFR4 p.Cys172Gly-Mutated Uveal Melanoma. The Role of Molecular Modelling in Personalized Oncology

• Published in: International journal of molecular sciences 2020-10, Vol.21 (21), p.8021
• Main Authors: Krebs, Fanny S, Gérard, Camille, Wicky, Alexandre, Aedo-Lopez, Veronica, Missiaglia, Edoardo, Bisig, Bettina, Trimech, Mounir, Michielin, Olivier, Homicsko, Krisztian, Zoete, Vincent
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Antineoplastic Agents - therapeutic use; Binding sites; Case reports; Conformation; Customization; Female; Fibroblast growth factor receptor 4; Fibroblasts; Growth factors; GTP-Binding Protein alpha Subunits, Gq-G11 - chemistry; GTP-Binding Protein alpha Subunits, Gq-G11 - genetics; GTP-Binding Protein alpha Subunits, Gq-G11 - metabolism; Humans; Immunoglobulins; Inhibitor drugs; Kinases; Ligands; MEK inhibitors; Melanoma; Melanoma - drug therapy; Melanoma - genetics; Melanoma - metabolism; Melanoma - pathology; Middle Aged; Modelling; Models, Molecular; Molecular modelling; Mutant Proteins - chemistry; Mutant Proteins - genetics; Mutant Proteins - metabolism; Mutation; Oncology; Pathogenicity; Protein Conformation; Protein Stability; Proteins; Pyridones - therapeutic use; Pyrimidinones - therapeutic use; Receptor, Fibroblast Growth Factor, Type 4 - chemistry; Receptor, Fibroblast Growth Factor, Type 4 - genetics; Receptor, Fibroblast Growth Factor, Type 4 - metabolism; Sequence Homology; Signal Transduction; Stability analysis; Structural analysis; Targeted cancer therapy; Uveal Neoplasms - drug therapy; Uveal Neoplasms - genetics; Uveal Neoplasms - metabolism; Uveal Neoplasms - pathology
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21218021

We report a case of an uveal melanoma patient with p.Gly48Leu who responded to MEK inhibition. At the time of the molecular analysis, the pathogenicity of the mutation was unknown. A tridimensional structural analysis showed that Gα can adopt active and inactive conformations that lead to substantial changes, involving three important switch regions. Our molecular modelling study predicted that p.Gly48Leu introduces new favorable interactions in its active conformation, whereas little or no impact is expected in its inactive form. This strongly suggests that p.Gly48Leu is a possible tumor-activating driver mutation, consequently triggering the MEK pathway. In addition, we also found an p.Cys172Gly mutation, which was predicted by molecular modelling analysis to lead to a gain of function by impacting the Ig-like domain 2 folding, which is involved in FGF binding and increases the stability of the homodimer. Based on these analyses, the patient received the MEK inhibitor trametinib with a lasting clinical benefit. This work highlights the importance of molecular modelling for personalized oncology.