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

Int J Mol Sci. 2020 Oct 28;21(21):8021. doi: 10.3390/ijms21218021.

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 Gαq 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: FGFR4; GNAQ; molecular modelling; mutation; precision oncology.

Publication types

  • Case Reports

MeSH terms

  • 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

Substances

  • Antineoplastic Agents
  • GNAQ protein, human
  • Mutant Proteins
  • Pyridones
  • Pyrimidinones
  • trametinib
  • FGFR4 protein, human
  • Receptor, Fibroblast Growth Factor, Type 4
  • GTP-Binding Protein alpha Subunits, Gq-G11

Supplementary concepts

  • Uveal melanoma