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

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.

Real-life use of trametinib after immunotherapy failure in BRAF wild-type advanced melanoma

“…Figure 1 illustrates all patients' OS and PFS. The median OS was 6.5 months (2-24), and the median PFS was 2 months (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). At the first evaluation (about 2 months following the beginning of treatment), eight patients (36%) had an objective disease control using RECIST criteria on computed tomography scan: six stable diseases and two partial responses.…”

“…In our study, patients with GNA11 and NF1 mutations were also included because of previous preclinical studies suggesting a sensibility to MEK inhibitors [4,5]. GNA Responses to trametinib: progression-free survival and overall survival.…”

“…In our study, patients with GNA11 and NF1 mutations were also included because of previous preclinical studies suggesting a sensibility to MEK inhibitors [4,5]. GNA is part of a gene family encoding G proteins with GTPase activity of down-regulation of cellular signalling [6].…”

“…NRAS Q61 mutations are harboured by 15% of melanomas [3]. Preclinical studies have suggested the effectiveness of MEK inhibitors on NRAS mutations, and on rarer mutations in GNA and NF1 genes [4][5][6]. Unfortunately, clinical trials with first-line MEK inhibitors (trametinib, binimetinib, cobimetinib) failed to demonstrate benefits in OS.…”

GNAQ mutations drive port wine birthmark-associated Sturge-Weber syndrome: A review of pathobiology, therapies, and current models

“…The p.Q209* mutations are predicted to cause more severe effects through overactivation of the MAPK pathway ( Schneider et al, 2019 ; Jain et al, 2020 ). GNAQ p.G48L mutation in UM is rare ( Krebs et al, 2020 ).…”