GNA11 Q209L

We were able to successfully conduct NGS studies in paraffin-embedded material archived for 10 years using both middlesized (OPA) and large (OCA v3) NGS panels. The identified S3FB1 mutation helps to explain the onset of metastases, even though the patient had spindle cell predominant UM with BAP-1 preservation, which are normally associated with decreased metastases risk. Our case highlights the value of using large NGS panels to unravel the molecular landscape of UM and further understand this unique eye cancer.

However, no clear association was found between any HLA genotype and survival. Results suggest a high potential immunogenicity of the GNAQ/11 Q209L variant that could allow the generation of novel therapeutic tools to treat UM like neoantigen vaccinations.

The established ddPCR assays are a valuable tool to detect the most frequent mutations in UM patients from ctDNA. These assays will allow serum and plasma genotyping, detection of MRD and monitoring of response to treatment to benefit UM patients and might support discrimination of uveal nevi from UM lesions.

Results may affect MUM care, treatment development, and trial stratification. More research is needed to confirm these findings.

Although these subprotocols did not meet the primary end point for ORR, significant responses or prolonged SD noted in some disease subtypes warrants further investigation.

A decrease in the proliferation and metabolic activity was observed in Mel285GNAQ-KO and Mel285BAP1-KO cell lines in comparison to the wildtype cells. Furthermore, an increase of phosphorylated ATF2/7 was noted in Mel285GNAQ-KO and Mel285GNA11-KO cell lines by western blotting.A better understanding of the altered pathways in our GNAQ/11 or BAP1 mutant isogenic cell lines will help to identify new drugs targeting specifically metastatic UM cells.

Although GNA11 mutation and CDKN2A loss significantly correlated with progression-free survival in our study, our sample size is small. The prognostic significance of GNAQ/GNA11 mutation and CDKN2A loss would require further investigation.

Our work also suggests a novel difference in sensitivity between the Gα Q209L, Gα Q209P, and Gα R183C mutants. We propose that disrupting the interaction between CA Gα and Gβγ can be a novel therapeutic target in UM.

We conclude that blue nevi can involve lymph nodes and are associated with benign clinical behavior, and probably represent so-called "benign" metastasis. Awareness of these lesions is important when evaluating lymph nodes to avoid misdiagnosis as metastatic melanoma.

We examined the activity of ASTX029, a novel dual-mechanism ERK inhibitor, which inhibits both the catalytic activity of ERK and its phosphorylation by MEK, and belinostat, a pan-HDAC inhibitor, in one GNAQQ209L- (92.1) and GNAQQ209P- (OMM1.3) and two GNA11Q209L-mutant (MP41, OMM1) uveal melanoma cell lines...We explored other drug candidates for combinatorial approaches including the BCL-2 inhibitor navitoclax, but no combination effect was observed...We also observed increased surface expression of immunological markers HLA-A, B, C (MHC Class 1), PD-L1, gp100 and MART-1. These results support that a combination strategy targeting ERK and HDAC in uveal melanoma should be investigated further.

Interestingly, Met-to-Death was longer in patients with GNAQ Q209P compared to GNAQ/GNA11 Q209L mutations, suggesting the difference in mutation type in GNAQ/GNA11 might determine the prognosis of MUM. Structural alterations of the GNAQ/GNA11 protein and their impact on survival of MUM patients should be further investigated.

One year later, intracranial extension of the melanocytoma necessitated a ventriculoperitoneal shunt and immunotherapy. Future work is needed to determine how GNA11 mutations in melanocytomas influence prognosis and monitoring strategies.

Our ddPCR assays will be a valuable tool to detect the most frequent genetic alterations in uveal melanoma patients from ctDNA. These assays will allow plasma genotyping, detection of MRD and monitoring of response to treatment.

Complete surgical resection was not possible and leptomeningeal metastatic disease rapidly ensued despite immunotherapy. Further understanding of the molecular signature may translate to improved diagnosis, prognostication and development of targeted therapies.

Here we found that YM-254890, a cyclic depsipeptide, inhibited downstream signaling induced by GNAQQ209L and GNA11Q209L, but not GNA14Q205L, GNA15Q212L and GNASQ227L in 293T cells, confirming that it is a GNAQ/11-specific inhibitor...Concordantly, an engineered GNA11 with the two mutations in cis was resistant to the compound. Our data suggest that targeting mutant GNAQ/11 is promising but will require combinatorial targeting of EDNR signaling and possibly other pathways to reach maximal clinical efficacy.

We sought to evaluate ctDNA in metastatic UM pts receiving experimental early phase clinical trial of LXS196, a PKCi, using digital droplet PCR (ddPCR) and targeted ion torrent next generation sequencing (NGS)... Baseline ctDNA correlates with baseline LDH level and disease volume. EOT ctDNA predicted clinical benefit to PKCi. The ctDNA AF derived from ddPCR and NGS was comparable and targeted ion torrent NGS was useful in detecting driver as well as additional mutations in UM.