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Copper ionophore elesclomol selectively targets GNAQ/11-mutant uveal melanoma

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.

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Fig. 1: Discovery of the GNAQ/11-specific compound elesclomol.
Fig. 2: Elesclomol selectively elevates intracellular ROS in GNAQ/11-mutant UM cells.
Fig. 3: Specific cellular events in elesclomol-treated GNAQ/11-mutant UM cells.
Fig. 4: Elesclomol impairs UM tumor growth in zebrafish and mouse models.
Fig. 5: Elesclomol selectively induces YAP phosphorylation in GNAQ/11-mutant UM cells.
Fig. 6: Elesclomol promotes YAP phosphorylation via ROS-induced Hippo signaling pathway activation.
Fig. 7: Antiproliferative effect of elesclomol on MEKi-resistant UM cells.
Fig. 8: Elesclomol regulates SNAI2 expression and cell migration through YAP.

Data availability

All sequencing data are available through the Gene Expression Omnibus (GEO) via accession code PRJNA733836.

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Acknowledgements

This research was supported by the National Natural Science Foundation of China (grant 82073889), the Science and Technology Commission of Shanghai (20DZ2270800), the Shanghai Municipal Science and Technology Major Project (19JC1410200), the National Facility for Translational Medicine (Shanghai) (TMSZ-2020-206), the Innovative Research Team of High-level Local Universities in Shanghai (SHSMU- ZDCX20210900), and startup funding of State Key Laboratory of Medical Genomics to JZ. We thank Drs. David E. Fisher and Xu Wu (Massachusetts General Hospital), Yantao Chen, and Yunqi Li (Shanghai Jiao Tong University) for review of this work and discussions on various topics relating to this project.

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JZ, YL, and JY designed and performed the experiments; JY, SX, and SG were responsible for the animal model; YL, JY, QZ, XX, and RJ analyzed the data; WS designed the ES analog ELE-003; YL, JZ, MJJ, and XF drafted the paper. All authors read and approved the final paper.

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Correspondence to Renbing Jia, Jianming Zhang or Xianqun Fan.

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For the patient-derived cell line and the tissue used for the PDX model, written informed consent was obtained from all involved patients. The process was approved by the ethics committee of Shanghai Ninth People’s Hospital (reference number: 20202356). For animal experiments, all procedures followed were in accordance with the Declaration of Helsinki. All animal research was conducted in accordance with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research, all procedures were reviewed and approved by Shanghai Ninth People’s Hospital Central Lab IACUC (Permit Number: SYXK (Shanghai) 2016-0016), and all experiments conformed to the relevant regulatory standards. The experimental design followed the Guide for the Care and Use of Laboratory Animals of AAALAC international.

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Li, Y., Yang, J., Zhang, Q. et al. Copper ionophore elesclomol selectively targets GNAQ/11-mutant uveal melanoma. Oncogene 41, 3539–3553 (2022). https://doi.org/10.1038/s41388-022-02364-0

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