Search

Your search keyword '"Krebs, Fanny S."' showing total 2 results
Start Over Author "Krebs, Fanny S." Topic gnaq
2 results on '"Krebs, Fanny S."'

1. 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.

Author

Krebs, Fanny S., Gérard, Camille, Wicky, Alexandre, Aedo-Lopez, Veronica, Missiaglia, Edoardo, Bisig, Bettina, Trimech, Mounir, Michielin, Olivier, Homicsko, Krisztian, and Zoete, Vincent

Subjects
*MOLECULAR models, *PROTEIN stability, *MELANOMA, *ONCOLOGY
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. [ABSTRACT FROM AUTHOR]

Published
2020
Full Text
View/download PDF

2. 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

Author

Krebs, Fanny S., Gerard, Camille, Wicky, Alexandre, Aedo-Lopez, Veronica, Missiaglia, Edoardo, Bisig, Bettina, Trimech, Mounir, Michielin, Olivier, Homicsko, Krisztian, and Zoete, Vincent

Subjects
phospholipase c-beta, gnaq, uniprot, precision oncology, fgfr4, mutation, protein, mutations, discovery, complex, molecular modelling
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 G alpha(q) 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.

Catalog

Books, media, physical & digital resources
See catalog results