Abstract 671: G-protein coupled receptor (GPCR) screening library identifies sertindole, an antipsychotic, as potential therapeutic option to target GNAQ mutation Q209L in uveal melanoma

Abstract

Abstract Background: Uveal melanoma is a rare but aggressive intraocular malignancy with limited therapeutic options. A hallmark genetic alteration associated with uveal melanoma is the mutation of the GNAQ gene, particularly the Q209L substitution in the Gαq protein, which contributes to oncogenic signaling and tumor progression. The GNAQ gene encodes for a Gαq protein that plays a critical role in signal transduction pathways involving G protein-coupled receptors (GPCRs). The Q209L substitution results in a gain-of-function mutation, leading to the chronic activation of downstream signaling pathways. This persistent signaling activity contributes to the uncontrolled growth of uveal melanoma cells. As G protein-coupled receptors (GPCRs) play a crucial role in this process, screening libraries of GPCR inhibitors has been explored as a potential therapeutic avenue. These libraries comprise a vast array of compounds with the potential to block or modulate GPCR activity. Identifying specific inhibitors that can effectively interfere with the oncogenic signaling cascades triggered by the mutated Gαq protein is a critical step in developing targeted therapies for uveal melanoma. Methods: GPCR library high throughput screening employed isogenic cell lines expressing wild type or mutant (Q209L) GNAQ. This process utilized IP-One assays to identify compounds affecting Gq-coupled receptors by detecting inositol monophosphate accumulation. Subsequently, promising hits were evaluated for their impact on inhibiting the growth and proliferation of uveal melanoma cells. Further analysis involved Western blotting to assess their potential in promoting autophagy and apoptosis, inhibiting downstream signaling pathways, and a migration assay. Finally, ROS generation was assessed using flow cytometry. Results: Using isogenic cell lines expressing GNAQ gene wild type and the Q209L mutant, a high-throughput screening of GPCR libraries identified sertindole among 5 hits. Sertindole showed a dose-dependent inhibition of Q209L-mutated uveal melanoma cells, significantly reducing cell viability, proliferation, and migration. It also suppressed key signaling pathways, including the critical MAPK pathway, and activated autophagy and apoptosis, likely via ROS generation. These findings suggest sertindole's multifaceted approach in suppressing cancer in uveal melanoma. Conclusion: Our study highlights the potential therapeutic value of sertindole in GNAQ Q209L-mutated uveal melanoma. Further research is needed to evaluate the efficacy of sertindole in preclinical mouse models of uveal melanoma. Citation Format: Shelby Rheinschmidt, Taylor Bargenquast, Sydney Adamson, Trason Thode, Alexis Weston, Tithi Ghosh Halder, Serina Ng, Harini Tulasi, Brian Durbin, Justin Moser, Mohan Kaadige, Raffaella Soldi, Sunil Sharma. G-protein coupled receptor (GPCR) screening library identifies sertindole, an antipsychotic, as potential therapeutic option to target GNAQ mutation Q209L in uveal melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 671.