G Protein-Coupled receptors and heterotrimeric G proteins as cancer drivers

Abstract

G protein-coupled receptors (GPCRs) and heterotrimeric G proteins play central roles in a diverse array of cellular processes. As such, dysregulation of GPCRs and their coupled heterotrimeric G proteins can dramatically alter the signalling landscape and functional state of a cell. Consistent with their fundamental physiological functions, GPCRs and their effector heterotrimeric G proteins are implicated in some of the most prevalent human diseases, including a complex disease such as cancer that causes significant morbidity and mortality worldwide. GPCR/G protein-mediated signalling impacts oncogenesis at multiple levels by regulating tumour angiogenesis, immune evasion, metastasis, and drug resistance. Here, we summarize the growing body of research on GPCRs and their effector heterotrimeric G proteins as drivers of cancer initiation and progression, and as emerging antitumoural therapeutic targets.

Keywords: G protein-coupled receptors; GTPases; angiogenesis; cancer; cancer metabolism; immune therapy; inflammation; metastasis; precision medicine; signal transduction.

Figure 1.. The Roles of G Proteins and GPCRs in the Hallmarks of Cancer:

Highlighted are representative G proteins and GPCRs with well-established roles as drivers of each cancer promoting hallmark. The centrality of GPCR signaling to cellular processes within and outside the tumor microenvironment through dysregulated oncocrine signaling networks promotes the development and progression of cancer. Refer to the text for details on each gene. Figure adapted from Hanahan and Weinberg, Cell, 2011.

Figure 2.. G Protein Mutation Distributions Across TCGA PanCancer Studies:

Lollipop plot depicting the mutation spectrum of A) GNAQ, B) GNA11, C) GNAS, and D) GNA13 across TCGA PanCancer studies. Missense mutations are depicted in green, and truncating mutations are depicted in black along the gene body. OncoKB annotated hotspot mutations are depicted in red below each gene. Pie charts represent distribution of cancer types where selected hotspots have been found. The data shown here are based upon data generated by the TCGA Research Network. All data was downloaded from cBio Portal^,.