GNAQ mutation

We examined the transcriptome of UM biopsies collected pre- and post-PKC inhibitor therapy and confirmed that MAPK, but not PI3K/AKT signalling, was inhibited early during treatment with the second-generation PKC inhibitor IDE196...We also show that re-activation of MAPK signalling has a dominant role in regulating PKC inhibitor responses in UM and that PI3K/AKT signalling diminishes UM cell sensitivity to PKC inhibitor monotherapy. Thus, combination therapies targeting PKC and PKC-independent signalling nodes, including PI3K/AKT activity, are required to improve responses in patients with metastatic UM.

Furthermore, in preclinical studies, actionable targets associated with BAP1 loss or oncogenic mutant SF3B1 have been identified, offering promising avenues for UM treatment. This review aims to summarize the emerging targeted and epigenetic therapeutic strategies for metastatic UM carrying specific driver mutations and the potential of combining these approaches with immunotherapy, with particular focus on those in upcoming or ongoing clinical trials.

Overexpression of oncogenic GnaqQ209L in the immortalized melanocyte cell line promoted in vivo growth that was enhanced by transgenic Hgf expression in the tumor microenvironment. This cross-signaling mechanism explains the selection of oncogenic Gnaq/11 in primary Hgf-Cdk4 melanomas and provides an example of how oncogenic driver mutations, intracellular signaling cascades, and microenvironmental cues cooperate to drive cancer development in a tissue-specific fashion.

Plaque-type blue naevi are diagnostically challenging tumours with risk for malignant transformation. Awareness and familiarity with the salient clinicopathological features are necessary for reliable diagnosis, and long-term clinical follow-up is required to monitor for malignant transformation.

As a result, more effective immunotherapeutic approaches, such as cancer vaccines, adoptive cell transfer, and other new molecules are currently being studied. In this review, we examine novel immunotherapeutic strategies in clinical and preclinical studies and highlight the latest insight in immunotherapy and the development of tailored treatment of UM.

NRAS mutation was found only in the abdominal tumor and was thought to be responsible for malignant progression in the present case. Multiregional comprehensive genetic analysis may lead to discovering novel driver mutations associated with tumorigenesis and targeted therapy.

Finally, we show that GNAQ/11-mutant UM cells and patients' tumors exhibit elevated levels of IP4, a biomarker of enhanced IP3 production; these high levels are abolished by GNAQ/11 inhibition and correlate with sensitivity to INPP5A depletion. Our findings uncover INPP5A as a synthetic lethal vulnerability and a potential therapeutic target for GNAQ/11-mutant-driven cancers.

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.

Noteworthy BRAF and ARID2 protein expression decreases detected in patients with their respective mutations. The integration of our analyses furnishes crucial insights into CRC's molecular characteristics, drug responsiveness, and the construction of a four-gene mutation signature for predicting CRC prognosis.

Our investigation reveals that darovasertib potently inhibits PKC as well as PKN/PRK, an AGC kinase family that is part of the "dark kinome." We find that downstream of the Gαq-RhoA signaling axis, PKN converges with ROCK to control FAK, a mediator of non-canonical Gαq-driven signaling. Strikingly, darovasertib synergizes with FAK inhibitors to halt UM growth and promote cytotoxic cell death in vitro and in preclinical metastatic mouse models, thus exposing a signaling vulnerability that can be exploited as a multimodal precision therapy against mUM.

Coupled with allele-specific PCR, it constitutes a sensitive platform for liquid biopsy detection, capable of sensing GNAQ Q209P in plasma samples with a low ctDNA concentration and fractional abundance. Finally, our method was validated using plasma samples from metastatic UM patients.

In this study, we treated GNAQ-mutant uveal melanoma cell lines with a Gαq/11 inhibitor, YM-254890, and conducted a kinase signaling proteomic screen using multiplexed-kinase inhibitors followed by mass spectrometry...Analysis of RNA-sequencing and proteomic data showed that Gαq signaling regulates STK10 expression and MARK3 activity. Our findings suggest an involvement of STK10 and MARK3 in the Gαq/11 oncogenic pathway and prompt further investigation into the specific roles and targeting potential of these kinases in uveal melanoma.

No abstract available

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.

Similarly, indirect attenuation of the YAP1/TAZ signaling pathway with an inhibitor of the mevalonate pathway, that is, the geranyl-geranyl transferase inhibitor GGTI-298, synergizes with Mcl-1 inhibition. This combination could be potentially used as a treatment for metastatic uveal melanoma.

Our findings indicate that melanomas with low melanocytic plasticity signature (MPS) expression possess the ability to employ various strategies to evade immune responses induced by immune checkpoint blockade (ICB). These strategies include: (1) transitioning to a mesenchymal-like state, (2) adapting through the suppression of inflammatory responses, and (3) upregulating the expression of alternative immune checkpoints. Currently, our research is focused on further validating these results and delving into the intricate mechanisms underlying these observations.

P2, N=4, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: May 2024 --> Dec 2025

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

Baseline ctDNA and LDH are prognostic factors while ctDNA clearance might predict benefit from Tebe. Other analyses are ongoing to identify new predictive biomarkers.

ctDNA was reduced in almost all pts. These data support the registrational phase II/III study for potential accelerated approval in 1L HLA-A2 neg. MUM, where there are no FDA approved therapies.

Both melanomas rapidly developed visceral metastases following diagnosis, with a fatal outcome in one case and tumor progression under palliative care in the other case. This data suggests that GRM1 gene fusions could represent an additional rare oncogenic driver in the setting of blue nevi, mutually exclusive of classical canonical mutations, especially in plaque-type or Ota subtypes.

It has been suggested that the presence of GNAQ mutations can differentiate leptomeningeal melanocytic neoplasms and uveal melanoma from MMNST. This case and others demonstrate that GNAQ mutations may exist in malignant nerve sheath tumors; that GNAQ and PRKAR1A mutations are not always mutually exclusive and that neither can be used to differentiate MMNST or MPNST from all melanocytic lesions.

P2, N=4, Active, not recruiting, National Cancer Institute (NCI) | N=35 --> 4

Furthermore, we demonstrated that these combinations exert a remarkable in vivo activity in UM patient-derived xenografts. Our study confirms the previously described synergy of the dual inhibition of FAK and MEK and identifies a novel combination of drugs (FAK and PKC inhibitors) as a promising strategy for therapeutic intervention in metastatic UM.

The cases highlight long relapse-free survival of UM; hence, a regular long-term follow-up should be mandatory. In addition, solitary metastases from UM should be treated, whenever possible, with a surgical approach, with complete removal as a goal.

In immunotherapy-treated patients, samples from responders showed higher TMB and lower LOH and were more frequently diploid compared to non-responders. Secondary germline testing and cfDNA analysis proved their efficacy in finding germline predisposing variants carriers (8.3%) and following dynamic changes during treatment as a surrogate of tissue biopsy, respectively.

GNAQ and GNA11 mutations were identified to be the most frequent mutations among UM patients, with a mutual exclusivity relationship between the two genes. New therapeutic modalities should consider the comprehensive genomic profiling of UM patients to improve their overall survival rate and quality of life.

Inhibition of NCOA3 activity inhibits several oncogenic pathways in a concerted manner, limiting UM cell survival and tumor growth. Our results deliver proof of concept that NCOA3 is a master transcriptional co-regulator of oncogenic signaling in uveal melanoma and a potential therapeutic target.

These observations together supported a scenario where the epigenomic rewiring associated to a selective genomic alteration, in this case the loss of one copy of chromosome 3, directs the acquisition of a new and aggressive phenotype. Current studies are focused on defining how these epigenomic alterations contribute towards the metastatic phenotype and identifying context-specific vulnerabilities associated with chromosome 3 copy-loss to develop novel therapeutics strategies to treat late-stage metastatic disease.

Finally, we complement our preclinical analyses with an investigation of spatial heterogeneity in a patient cohort of paired primary and metastatic tumors. More broadly, comparing these D3 vs. M3 signatures provides an opportunity to expand on our knowledge of metastatic disease drivers and derive prognostic signatures associated with poor survival.

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.

Further analysis demonstrated that FAK activates PI3K through the association and tyrosine phosphorylation of the p85 regulatory subunit of PI3K, and that UM cells require PI3K/AKT signaling for survival. These findings establish a novel link between Gαq-driven signaling and the stimulation of PI3K, as well as demonstrate aberrant activation of signaling networks underlying the growth and survival of UM and other Gαq-driven malignancies.

This study is the first to report ctDNA detection rate and prognostic impact in UM patients eligible for surgical resection of their liver metastases. If confirmed by further studies in this setting, this non-invasive biomarker could inform treatment decisions in UM patients with liver metastases.

MiR-181a-5p also decreased the expression of Ki67, GNAQ, and AKT3, and induced the expression of cleaved-caspase3 in UM tumors. These results suggest that miR-181a-5p inhibits UM development by targeting GNAQ and AKT3.

A greater proportion of small UM have a favorable molecular prognostic profile compared to larger UM. However, a greater proportion of small UM are still genetically evolving compared to larger UM, suggesting that some may have progress to a poor prognostic profile if allowed to grow untreated. These findings represent the most comprehensive molecular analysis of small UM to date, and they provide an evidence-based framework for developing management guidelines.

The molecular characteristics of Korean uveal melanoma patients were largely similar to those of Western patients, except for relatively higher frequency of 8q gain, which appears to develop in eariler ages before clinical dignosis of tumors.

P2, N=35, Active, not recruiting, National Cancer Institute (NCI) | Trial primary completion date: Oct 2022 --> May 2023

Some of the biggest hurdles preventing development of new therapeutics are unanswered questions regarding disease biology and lack of models for drug screening. In this review, we discuss the current understanding of GNAQ signaling, the standard of care for patients, overlap with other GNAQ-associated or phenotypically similar diseases, as well as deficiencies in current in vivo and in vitro vascular malformation models.

The remainder of the DN had nonspecific mutations in various signaling pathways with few progression mutations. Overall, our study provides preliminary data that next-generation sequencing data may have the potential to serve as an ancillary diagnostic tool to help differentiate malignant and benign desmoplastic melanocytic neoplasms.