Concurrent Targeting of Glutaminolysis and Metabotropic Glutamate Receptor 1 (GRM1) Reduces Glutamate Bioavailability in GRM1 + Melanoma

• Published in: Cancer research (Chicago, Ill.) Vol. 79; no. 8; pp. 1799 - 1809
• Main Authors: Shah, Raj, Singh, Simar J, Eddy, Kevinn, Filipp, Fabian V, Chen, Suzie
• Format: Journal Article
• Language: English
• Published: United States 15.04.2019
• Subjects: Animals; Apoptosis; Benzeneacetamides - pharmacology; Biological Availability; Cell Proliferation; Drug Therapy, Combination; Female; Glutamic Acid - metabolism; Glutaminase - antagonists & inhibitors; Humans; Melanoma - drug therapy; Melanoma - metabolism; Melanoma - pathology; Mice; Mice, Hairless; Neuroprotective Agents - pharmacology; Receptors, Metabotropic Glutamate - antagonists & inhibitors; Riluzole - pharmacology; Signal Transduction; Thiadiazoles - pharmacology; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-18-1500

Aberrant glutamatergic signaling has been implicated in altered metabolic activity in many cancer types, including malignant melanoma. Previously, we have illustrated the role of metabotropic glutamate receptor 1 (GRM1) in neoplastic transformation of melanocytes and spontaneous metastatic melanoma . In this study, we showed that autocrine stimulation constitutively activates the GRM1 receptor and its downstream mitogenic signaling. GRM1-activated (GRM1 ) melanomas exhibited significantly increased expression of glutaminase (GLS), which catalyzes the first step in the conversion of glutamine to glutamate. In cultured GRM1 melanoma cell lines, CB-839, a potent, selective, and orally bioavailable inhibitor of GLS, suppressed cell proliferation, while riluzole, an inhibitor of glutamate release, promoted apoptotic cell death and . Combined treatment with CB-839 and riluzole treatment proved to be superior to single-agent treatment, restricting glutamate bioavailability and leading to effective suppression of tumor cell proliferation and tumor progression . Hyperactivation of GRM1 in malignant melanoma is an oncogenic driver, which acts independently of canonical melanoma proto-oncogenes, BRAF or NRAS. Overall, these results indicate that expression of GRM1 promotes a metabolic phenotype that supports increased glutamate production and autocrine glutamatergic signaling, which can be pharmacologically targeted by decreasing glutamate bioavailability and the GLS-dependent glutamine to glutamate conversion. SIGNIFICANCE: These findings demonstrate that targeting glutaminolytic glutamate bioavailability is an effective therapeutic strategy for GRM1-activated tumors.