Abstract 5677: Targeting G protein-coupled receptors in cancer pharmacotherapy: a comprehensive screening platform establishment and application in drug discovery

Abstract G protein-coupled receptors (GPCRs) constitute the largest family of membrane protein family in the human genome with over 800 members. They play an important role in various physiological and physiological processes and, such as proliferation, differentiation, neurotransmission, development and apoptosis. Several studies demonstrated that GPCRs play significant roles in the development of cancer, with their involvement in the initiation, growth, and spread of tumors being well-established. Several drugs targeting different GPCRs have been approved for the treatment of cancers, including CXCR4 (C-X-C chemokine receptor type 4) antagonism has been demonstrated to interfere with the communication between tumors and their surrounding stroma, enhance the susceptibility of cancer cells to chemotherapy, and reduce tumor growth and metastatic burden, GnRH (gonadotropin-releasing hormone) antagonists, which are used to treat hormone-dependent tumors like prostate cancer and breast cancer. Despite the increasing recognition of GPCRs' critical functions in cancer pathogenesis, it is noteworthy that only a small number of GPCR targets have been successfully leveraged for the development of anti-cancer treatments. Consequently, comprehensive compound screening platform is particularly important for highlighting the potential of pharmacologically modulating these GPCRs for the development of novel anti-cancer therapeutics. This research established stable cell lines expressing GPCRs and constructed multiple assay modes for GPCR drug discovery and screening, including in vitro HTRF cAMP assay, calcium flux assay and β-arretin2 NanoBiT assay, which can be used for agonist, antagonist and inverse agonist validation. Meanwhile, several CDX modes are constructed for promisingly conducting in-vivo experiments and biomarker detection. Thus, our GPCR platform can provide comprehensive screening cascade for compound evaluation, support multiple approaches to facilitate anti-cancer drug discovery. Citation Format: Xiaoyan Wang, Dandan Hu, Ziwei Zhang, Tj (Tiejun) Bing. Targeting G protein-coupled receptors in cancer pharmacotherapy: a comprehensive screening platform establishment and application in drug discovery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5677.