Harnessing the genome for characterization of G-protein coupled receptors in cancer pathogenesis

Abstract

G-protein coupled receptors (GPCRs) mediate numerous physiological processes and represent the targets for a vast array of therapeutics for diseases ranging from depression to hypertension to reflux. Despite the recognition that GPCRs can act as oncogenes and tumour suppressors by regulating oncogenic signalling networks, few drugs targeting GPCRs are utilized in cancer therapy. Recent large-scale genome-wide analyses of multiple human tumours have uncovered novel GPCRs altered in cancer. However, work aiming to determine which GPCRs from these lists are the drivers of tumourigenesis, and hence valid therapeutic targets, comprises a formidable challenge. The present review highlights recent studies providing evidence that GPCRs are relevant targets for cancer therapy through their effects on known cancer signalling pathways, tumour progression, invasion and metastasis, and the microenvironment. Furthermore, the review also explores how genomic analysis is beginning to highlight GPCRs as therapeutic targets in the age of personalized medicine.

Keywords: GPCR; bioinformatics; cancer; genomics; metastasis; microenvironment; signal transduction.

Figure

GPCRs regulate multiple steps in cancer progression, including initiation, metastatic dissemination and secondary niche maintenance, through a wide array of signaling effectors. This diversity may provide novel avenues for GPCR-targeted therapeutics in the treatment of cancer. Abbreviations: STAT3 (signal transducer and activator of transcription 3), PI3K (phosphoinositide 3-kinase), MAPK (mitogen activated protein kinase), EGFR (epidermal growth factor receptor), PAR-1 (protease activated receptor 1), VHL (von Hippel-Lindau), HIF2 (hypoxia-inducible factor 2), cAMP (cyclic adenosine monophosphate), PKA (protein kinase A), S1PR1 (sphingosine-1-phosphate receptor 1).