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Copper ionophore elesclomol selectively targets GNAQ/11-mutant uveal melanoma
Yongyun Li1,2, Jie Yang1,2, Qianqian Zhang3
1Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Abstract:
Unlike cutaneous melanoma, uveal melanoma (UM) is characterized by mutations in GNAQ and GNA11 and remains a fatal disease because there is essentially no effective targeted therapy or immunotherapy available. We report the discovery of the copper ionophore elesclomol as a GNAQ/11-specific UM inhibitor. Elesclomol was identified in a differential cytotoxicity screen of an in-house tool compound library, and its in vivo pharmacological efficacy was further confirmed in zebrafish and mouse UM models. Mechanistically, elesclomol transports copper to mitochondria and produces a large amount of reactive oxygen species (ROS) as Cu(II) is reduced to Cu(I) in GNAQ/11-mutant UM cells, which selectively activates LATS1 kinase in the Hippo signaling pathway and consequently promotes YAP phosphorylation and inhibits its nuclear accumulation. The inactivation of YAP downregulates the expression of SNAI2, which in turn suppresses the migration of UM cells. These findings were cross validated by our clinical observation that YAP activation was found specifically in UM samples with a GNAQ/11 mutation. Furthermore, addition of binimetinib, a MEK inhibitor, to elesclomol increased its synthetic lethality to GNAQ/11-mutant UM cells, thereby overriding drug resistance. This effect was confirmed in an orthotopic xenograft model and in a patient-derived xenograft model of UM. These studies reveal a novel mechanistic basis for repurposing elesclomol by showing that copper homeostasis is a GNAQ/11-specific vulnerability in UM. Elesclomol may provide a new therapeutic path for selectively targeting malignant GNAQ/11-mutant UM.
Insights
Researchers discovered elesclomol, a copper ionophore, as a targeted therapy for GNAQ/11-mutant uveal melanoma (UM). This drug selectively kills UM cells by disrupting copper homeostasis and inhibiting YAP signaling, offering a new therapeutic avenue for this fatal disease.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Uveal melanoma (UM) with GNAQ/11 mutations lacks effective treatments.
- Current targeted therapies and immunotherapies are largely ineffective for UM.
Purpose of the Study:
- To identify novel therapeutic targets and drugs for GNAQ/11-mutant uveal melanoma.
- To elucidate the mechanism of action for a novel UM inhibitor.
Main Methods:
- Differential cytotoxicity screening to identify potential drug candidates.
- In vivo efficacy studies in zebrafish and mouse UM models.
- Mechanistic studies involving reactive oxygen species (ROS) production, Hippo signaling pathway activation, and YAP/SNAI2 regulation.
- Combination therapy studies with binimetinib (MEK inhibitor).
Main Results:
- Elesclomol identified as a GNAQ/11-specific inhibitor of UM.
- Elesclomol induces ROS production and selectively activates LATS1 kinase, leading to YAP inactivation in GNAQ/11-mutant UM cells.
- YAP inactivation downregulates SNAI2, suppressing UM cell migration.
- Combination of elesclomol and binimetinib demonstrates synthetic lethality and overcomes drug resistance in UM models.
Conclusions:
- Copper homeostasis is a GNAQ/11-specific vulnerability in UM.
- Elesclomol represents a promising new therapeutic strategy for targeting malignant GNAQ/11-mutant UM.
- Repurposing elesclomol offers a potential new treatment path for this aggressive cancer.
