5. Challenges and opportunities of targeting GPCRs in cancer

Targeting GPCRs including those harboring mutations in cancer therapy presents a dual landscape of challenges and opportunities. One significant challenge lies in the diversity of GPCRs and their intricate signaling networks including crosstalk with various cellular processes. This will bring potential off-target effects and unintended consequences on normal physiological functions, which make it complex to develop broad-spectrum therapeutic interventions. Furthermore, identification of cancer specific GPCR mutations while distinguishing them from natural variants is another hurdle, requiring advanced genomic and bioinformatics analyses. One of the primary challenges in this field is the limited availability and accessibility of comprehensive datasets. GPCR research suffers from relatively small and scattered datasets, which can impede the identification of robust associations between GPCR mutations and cancer. For example, when comparing the mutational landscape of GPCRs with the mutations in kinases, GPCRs mostly have widespread mutations with few identified clustering, while kinases feature distinct mutational hotspots (Dixit et al. , 2009). The absence of clearly defined structural hotspot mutations in GPCRs imply that targeting GPCRs in cancer is more challenging compared to the well-studied approach targeting kinases. However, promising opportunities are present in cancer drug development targeting GPCRs, especially those overexpressed in cancer cells (R. T. Dorsam & J. S. Gutkind, 2007) and those involved in anti-cancer immunomodulation (Qiu, Yu, & Ma, 2024). In recent years, antibodies have shown the potential to revolutionize GPCR-targeted therapies with their high specificity and affinity. Modified antibodies directed against specific GPCRs can serve as precision tools, enabling treatment with reduced off-target effects. For example, the first-in-class CCR4 antibody drug named Mogamulizumab has been approved for treatment of T-cell leukemia-lymphoma with enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) activity (Beck & Reichert, 2012). Additionally, novel allosteric modulators present a unique opportunity in GPCR-targeted cancer therapy. By modulating GPCR activity via non-competitive binding sites, allosteric modulators allow for a more nuanced regulation of signaling pathways. This fine-tuned control can offer advantages in specificity and selectivity, potentially avoiding side effects associated with orthosteric ligands (Bartfai & Wang, 2013). Another opportunity lies in the usage of unbiased “GPCRome” datasets. The concept of the GPCRome refers to the comprehensive exploration of GPCR gene expression, copy number variation, mutational signatures and functions, offering a system level understanding of their roles in cancer biology (Wu et al. , 2019). Leveraging the GPCRome could facilitate the discovery of novel biomarkers for early diagnose of cancer, and also accelerate drug discovery by identifying previously overlooked GPCRs as potential therapeutic targets, highlighting their signaling network, and uncovering their interactions within the tumor microenvironment. For example, Arora et al . performed a comprehensive analysis of extracellular GPCR networks in cancer transcriptomic datasets, and found that many ligand-receptor axes, including muscarinic, adenosine, 5-hydroxytryptamine and chemokine receptors, are associated with patient survival and can be exploited to inhibit cancer cell growth (C. Arora et al. , 2024). Furthermore, the advent of single-cell GPCRomics has allowed researchers to unravel the heterogeneity within cancer cell populations (P. A. Insel et al. , 2019), and AI-driven structural biological studies have enhanced our ability to understand the complexity of GPCR signaling networks (Matic, Miglionico, Tatsumi, Inoue, & Raimondi, 2023). Besides, experimental tools such as the PRESTO-Tango assay facilitates systematic interrogation of GPCR signaling by coupling receptor activation to a reporter system, uncovering novel druggable targets (Kroeze et al. , 2015). Alternative methods such as DNA-encoded library (DEL) screening and CRISPR-based profiling offer high-throughput platforms to identify GPCR ligands and evaluate the functional consequences of genetic alterations (Cai, El Daibani, Bai, Che, & Krusemark, 2023; Kapolka et al. , 2020). Lastly, quantitative mass spectrometry in combination with proximity labeling techniques such as BioID or APEX enables precise mapping of context-dependent GPCR signaling networks and post-translational modifications (Paek et al. , 2017). These advancements of in silico and experimental techniques will together make GPCR targeting in cancer a promising field.