FR900359 and Melanoma

Uveal melanoma is the most common primary intraocular malignant tumor in adults and arises from the transformation of melanocytes in the uveal tract. Even after treatment of the primary tumor, up to 50% of patients succumb to metastatic disease. The liver is the predominant organ of metastasis. There is an important need to provide effective treatment options for advanced stage uveal melanoma. To provide the preclinical basis for new treatments, it is important to understand the molecular underpinnings of the disease. Recent genomic studies have shown that mutations within components of G protein-coupled receptor (GPCR) signaling are early events associated with approximately 98% of uveal melanomas.

Topics: Antineoplastic Agents; Clinical Trials as Topic; Depsipeptides; Genetic Predisposition to Disease; GTP-Binding Protein alpha Subunits; GTP-Binding Protein alpha Subunits, Gq-G11; Humans; Melanoma; Mutation; Neoplasm Metastasis; Receptors, G-Protein-Coupled; Signal Transduction; Uveal Neoplasms

Uveal melanoma is the most common intraocular tumor in adults and often metastasizes to the liver, leaving patients with few options. Recurrent activating mutations in the G proteins, Gα

Topics: Animals; Cell Growth Processes; Cell Line, Tumor; Depsipeptides; GTP-Binding Protein alpha Subunits; GTP-Binding Protein alpha Subunits, Gq-G11; Guanosine 5'-O-(3-Thiotriphosphate); Humans; Insecta; MAP Kinase Signaling System; Melanoma; Rats; Recombinant Proteins; Uveal Neoplasms

Somatic gain-of-function mutations of

Topics: Animals; Cell Line, Tumor; Depsipeptides; Drug Delivery Systems; Gain of Function Mutation; GTP-Binding Protein alpha Subunits; GTP-Binding Protein alpha Subunits, Gq-G11; HEK293 Cells; Humans; Melanoma; Mice; Mice, Inbred NOD; Mice, SCID; Neoplasm Proteins; Uveal Neoplasms; Xenograft Model Antitumor Assays

Despite the discovery of heterotrimeric αβγ G proteins ∼25 years ago, their selective perturbation by cell-permeable inhibitors remains a fundamental challenge. Here we report that the plant-derived depsipeptide FR900359 (FR) is ideally suited to this task. Using a multifaceted approach we systematically characterize FR as a selective inhibitor of Gq/11/14 over all other mammalian Gα isoforms and elaborate its molecular mechanism of action. We also use FR to investigate whether inhibition of Gq proteins is an effective post-receptor strategy to target oncogenic signalling, using melanoma as a model system. FR suppresses many of the hallmark features that are central to the malignancy of melanoma cells, thereby providing new opportunities for therapeutic intervention. Just as pertussis toxin is used extensively to probe and inhibit the signalling of Gi/o proteins, we anticipate that FR will at least be its equivalent for investigating the biological relevance of Gq.

Topics: Animals; Ardisia; Cell Line, Tumor; Depsipeptides; Gene Expression Regulation, Neoplastic; GTP-Binding Protein alpha Subunits, Gq-G11; Humans; Melanoma; Mice; Models, Molecular; Molecular Structure; Protein Conformation; Protein Isoforms; Signal Transduction; Tail; Vasoconstriction