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.

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Version: Final published version
License: CC BY 4.0
Serval ID
serval:BIB_44F221AEB60A
Type
Article: article from journal or magazin.
Publication sub-type
Case report (case report): feedback on an observation with a short commentary.
Collection
Publications
Institution
Title
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.
Journal
International journal of molecular sciences
Author(s)
Krebs F.S., Gérard C., Wicky A., Aedo-Lopez V., Missiaglia E., Bisig B., Trimech M., Michielin O., Homicsko K., Zoete V.
ISSN
1422-0067 (Electronic)
ISSN-L
1422-0067
Publication state
Published
Issued date
28/10/2020
Peer-reviewed
Oui
Volume
21
Number
21
Pages
E8021
Language
english
Notes
Publication types: Case Reports ; Journal Article
Publication Status: epublish
Abstract
We report a case of an uveal melanoma patient with GNAQ 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 <sub>q</sub> can adopt active and inactive conformations that lead to substantial changes, involving three important switch regions. Our molecular modelling study predicted that GNAQ 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 GNAQ p.Gly48Leu is a possible tumor-activating driver mutation, consequently triggering the MEK pathway. In addition, we also found an FGFR4 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.
Keywords
Amino Acid Sequence, Antineoplastic Agents/therapeutic use, Female, 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, Melanoma/drug therapy, Melanoma/genetics, Melanoma/metabolism, Melanoma/pathology, Middle Aged, Models, Molecular, Mutant Proteins/chemistry, Mutant Proteins/genetics, Mutant Proteins/metabolism, Mutation, Protein Conformation, Protein Stability, 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, Uveal Neoplasms/drug therapy, Uveal Neoplasms/genetics, Uveal Neoplasms/metabolism, Uveal Neoplasms/pathology, FGFR4, GNAQ, molecular modelling, mutation, precision oncology
Pubmed
Web of science
Open Access
Yes
Create date
02/11/2020 10:49
Last modification date
07/04/2021 6:34
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