Figure 1 G protein-mediated signaling pathway of GPCRs. Ligand-induced conformational change leads to activation of the heterotrimeric G protein, resulting in dissociation of the Gα subunit from the Gβγ subunits. Downstream effects of secondary messengers lead to an ultimate cellular response. Figure was made with adobe illustrator and adapted from Dorsam and Gutkind (Robert T Dorsam & J Silvio Gutkind, 2007).

2.2 Aberrant GPCR expression in cancer

Comparing to healthy tissues, aberrant expression of GPCRs are frequently observed in several types of tumors (Kübler & Albrecht, 2018; Perez Almeria, Setiawan, Siderius, & Smit, 2021). Especially in tumors of the neuroendocrine system, overexpression of GPCRs is highly prevalent, such as MC2R, 5-HT4R, LHCGR, GnRHR, TRHR, GLP1R, GIPR, and GRP101 (Lacroix et al. , 2024). It has also been reported that in pancreatic ductal adenocarcinoma, overexpression of multiple GPCRs, such as HRH1, LPAR5 and CCR6, tends to be more prevalent than common oncogenic mutations such as KRAS and TP53 (Sriram, Moyung, Corriden, Carter, & Insel, 2019). In addition, Arora et al. found that almost every cancer subtype is characterized by a highly specific GPCR-ligand co-expression signature, and they identified clusters of GPCR-ligand pairs showing a prevalence of concordant upregulation or downregulation across cancer subtypes. Furthermore, in some subtypes featured with the co-downregulated GPCR axes, concomitant mutations of several tumor suppressor genes are present. While in the concordantly upregulated axes, cancer subtypes with Gα12/13prevalence are characterized by mutations of the KRAS, PIK3CA, and MLLT3 oncogenes. Importantly, they also found that the expression of GPCR genes is associated with lower or higher survival of cases depending on cancer subtype, while some receptors show consistent associations among subtypes. For example, ADORA2A is associated with higher survival across four cancer tissues (pancreas, breast, skin, and head and neck), while GPCRs such as OXTR, ADORA2B, GPR3, FZD6 are invariably associated with poorer survival. To be noted, there is not always consistency between the association of receptor expression on patient survival with the direct effects of receptor activation/inhibition on cancer cells. For example, when HEPG2 cells were treated with either an ADORA2A or ADORA2B inhibitor, they observed that the cell viability was significantly decreased in a dose-dependent manner for both (C. Arora et al. , 2024). Many factors including cancer subtype, receptor crosstalk, and cell-cell interactions within the tumor microenvironment can play a role, making drug effects on patients hard to predict. Despite the complexity, these findings indicate that aberrant GPCR expression could play an important role in cancer progression and prognosis.

2.3 GPCR signaling in cancer development

In cancer, GPCR signaling can impact crucial characteristics of cancer development, such as uncontrolled cell growth, achieving replicative immortality, resisting apoptosis, initiating invasion and metastasis (New & Wong, 2007; O’Hayre, Degese, & Gutkind, 2014). The role that different downstream signaling pathways play is summarized below.