Functional characterization of uveal melanoma oncogenes

  title={Functional characterization of uveal melanoma oncogenes},
  author={Jiafang Ma and Li Weng and Boris C. Bastian and Xu Chen},
  pages={806 - 820}
Uveal melanoma (UM) is a currently untreatable form of melanoma with a 50% mortality rate. Characterization of the essential signaling pathways driving this cancer is critical to develop target therapies. Activating mutations in the Gαq signaling pathway at the level of GNAQ, GNA11, or rarely CYSLTR2 or PLCβ4 are considered alterations driving proliferation in UM and several other neoplastic disorders. Here, we systematically examined the oncogenic signaling output of various mutations… 

Uveal melanoma–associated mutations in PLCβ4 are constitutively activating and promote melanocyte proliferation and tumorigenesis

The findings reveal that PLCβ4 mediates oncogenic signaling in UM, and thus, targeting known mediators downstream of PLC β4 (such as the kinase MEK, for which inhibitors exist) may be effective at treating this subset of UM.

The ERK signaling pathway returns to the limelight in uveal melanomas

The authors demonstrate that oncogenic GNAQ/11 stimulates the PLCβPKC axis, whose signal then branches into the MEKERK and FAKYAP pathways, which indicates that the FAK/YAP element does not prevail in UM cell proliferation and survival.

Protein kinase inhibitor responses in uveal melanoma reflects a diminished dependency on PKC-MAPK signaling.

This study examined the signaling and functional effects of two PKC inhibitors in a panel of UM cell models and found that UM cell show complex, PKC-independent signaling pathways that contribute to their survival and resistance to targeted therapies.

Targeting GNAQ/11 through PKC inhibition in uveal melanoma.

Molecular profiling over the past decade has helped define uveal melanomas by characteristic mutations: GNAQ, GNA11, BAP1, SF3B1, and EIF1AX mutations.

Targeting Oncogenic Gαq/11 in Uveal Melanoma

Pre-clinical and clinical studies that have attempted to understand and treat uveal melanoma by inhibiting the Gq/11 signaling pathway are summarized and recent efforts to target Gq and G11 in mouse models are discussed.

Integrated analysis reveals the dysfunction of signaling pathways in uveal melanoma

The potential key signals for occurrence and metastasis of Uveal melanoma are discovered and a theoretical basis for potential clinical application is provided.

GNAQ and GNA11 Genes: A Comprehensive Review on Oncogenesis, Prognosis and Therapeutic Opportunities in Uveal Melanoma

This review aims to provide a current comprehensive view of what the authors know about GNAQ and GNA11 genes on oncogenesis, prognosis and therapeutic opportunities in uveal melanoma.

Cutaneous and uveal melanoma: two different cancers in therapeutic needs.

The mutation of MITF, the master gene of melanocyte homeostasis, is identified as a new melanoma predisposition gene in cutaneous melanoma, and the recent findings of intratumor heterogeneity and characterization of cell sub-populations in primary uveal melanomas offer new tools for early detection and therapeutic targets.



Combined PKC and MEK inhibition in uveal melanoma with GNAQ and GNA11 mutations

PKC is identified as a rational therapeutic target for melanoma patients with GNAQ or GNA11 mutations and combined MEK and PKC inhibition is synergistic, with superior efficacy compared to treatment with either approach alone, and combined PKC and MEK inhibition was efficacious in vivo, causing marked tumor regression in a UM xenograft model.

Direct targeting of Gαq and Gα11 oncoproteins in cancer cells

It is reported that the cyclic depsipeptide FR900359 directly interacted with GTPase-deficient Gαq/11 proteins and preferentially inhibited mitogenic ERK signaling rather than canonical phospholipase Cβ (PLCβ) signaling driven by these oncogenes.

Effects of Oncogenic Gαq and Gα11 Inhibition by FR900359 in Uveal Melanoma

It is found that the Gαq/11 inhibitor, FR900359 (FR), effectively inhibits oncogenic GαQ/11 signaling in uveal melanoma cells expressing either mutant G αq or Gα11, and colony formation is prevented by FR treatment by 3D-cell culture, providing promise for future in vivo studies.

Mutant Gq/11 promote uveal melanoma tumorigenesis by activating YAP.

Frequent Mutation of BAP1 in Metastasizing Uveal Melanomas

Exome capture coupled with massively parallel sequencing is used to search for metastasis-related mutations in highly metastatic uveal melanomas of the eye and implicate loss of BAP1 in uveAL melanoma metastasis and suggest that the BAP 1 pathway may be a valuable therapeutic target.

Recurrent activating mutations of G-protein-coupled receptor CYSLTR2 in uveal melanoma

It is found that a recurrent mutation in CYSLTR2 (cysteinyl leukotriene receptor 2) encoding a p.Leu129Gln substitution in 4 of 9 samples that lacked mutations in GNAQ, GNA11, and PLCB4 but in 0 of 127 samples that harbored mutations in these genes.