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Open AccessArticle

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

1
Computer-aided molecular engineering group, Department of Fundamental Oncology, Lausanne University, Ludwig Lausanne Branch, 1066 Epalinges, Switzerland
2
Precision Oncology Center, Department of Oncology, Lausanne University Hospital, 1011 Lausanne, Switzerland
3
Service of Medical Oncology, Department of Oncology, Lausanne University Hospital, 1011 Lausanne, Switzerland
4
SIB Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland
5
University Institute of Pathology, Lausanne University Hospital, 1011 Lausanne, Switzerland
6
Laboratory of Translational Oncology, EPFL, 1015 Lausanne, Switzerland
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(21), 8021; https://doi.org/10.3390/ijms21218021
Received: 22 September 2020 / Revised: 20 October 2020 / Accepted: 22 October 2020 / Published: 28 October 2020
(This article belongs to the Section Molecular Oncology)
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. View Full-Text
Keywords: precision oncology; molecular modelling; mutation; GNAQ; FGFR4 precision oncology; molecular modelling; mutation; GNAQ; FGFR4
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MDPI and ACS Style

Krebs, F.S.; Gérard, C.; Wicky, A.; Aedo-Lopez, V.; Missiaglia, E.; Bisig, B.; Trimech, M.; Michielin, O.; Homicsko, K.; Zoete, V. 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, 21, 8021. https://doi.org/10.3390/ijms21218021

AMA Style

Krebs FS, Gérard C, Wicky A, Aedo-Lopez V, Missiaglia E, Bisig B, Trimech M, Michielin O, Homicsko K, Zoete V. 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. International Journal of Molecular Sciences. 2020; 21(21):8021. https://doi.org/10.3390/ijms21218021

Chicago/Turabian Style

Krebs, Fanny S.; Gérard, Camille; Wicky, Alexandre; Aedo-Lopez, Veronica; Missiaglia, Edoardo; Bisig, Bettina; Trimech, Mounir; Michielin, Olivier; Homicsko, Krisztian; Zoete, Vincent. 2020. "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. 21, no. 21: 8021. https://doi.org/10.3390/ijms21218021

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