Trametinib Induces the Stabilization of a Dual <i>GNAQ</i> p.Gly48Leu- and <i>FGFR4</i> p.Cys172Gly-Mutated Uveal Melanoma. The Role of Molecular Modelling in Personalized Oncology
We report a case of an uveal melanoma patient with <i>GNAQ</i> 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 an...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2020-10-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/21/21/8021 |
| Summary: | We report a case of an uveal melanoma patient with <i>GNAQ</i> 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 <i>GNAQ</i> 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 <i>GNAQ</i> p.Gly48Leu is a possible tumor-activating driver mutation, consequently triggering the MEK pathway. In addition, we also found an <i>FGFR4</i> 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. |
|---|---|
| ISSN: | 1661-6596 1422-0067 |