Table 1.
Gi/o-coupled receptor agonists and Gs-coupled receptor antagonists with known or putative anti-cancer activity
| GPCR | Cancers | Agonists | Evidence for therapeutic benefit in cancer | Indications |
|---|---|---|---|---|
| Gi/o-coupled receptors with high expression, with no change in expression in tumor compared to wild-type, and with approved agonists | ||||
| ADORA3 | BLCA | 2 | Antiproliferative effects of adenosine or synthetic agonist in melanoma, prostate, colon and liver carcinomas or lymphoma [70, 71] | Coronary vasodilators, pharmacological stress testing |
| HNSC | ||||
| LUSC | ||||
| PRAD | ||||
| STAD | ||||
| HTR1D | STAD | 20 | Serotonin analogues are inhibitors of breast cancer cell growth [72] | Agonists used for migrane treatment |
| S1PR1 | ESCA | 1 | Fingolimod efficacy in in-vitro and in-vivo cancer models by inhibition of sphingosine kinase 1 [73] + | Immuno-modulating in Multiple Sclerosis |
| READ | ||||
| STAD | ||||
| SSTR1 | ESCA | 1 | Pasireotide (somatostatin analogue) can inhibit non-functioning pituitary adenomas and neuroendocrine tumors [74, 75] | Treatment of Cushing’s disease |
| KIRP | ||||
| LIHC | ||||
| STAD | ||||
| UCEC | ||||
| Gs-coupled receptors with no significant under expression and with approved antagonists | ||||
| ADRA2A | ESCA | 11 | None found | Many indications for antagonists, including Parkinson’s, schizophrenia, psychosis, depression and erectile dysfunction |
| HNSC | ||||
| LUSC | ||||
| READ | ||||
| STAD | ||||
| THCA | ||||
| UCEC | ||||
| ADRA2B | KICH | 13 | None found | As above |
| KIRC | ||||
| UCEC | ||||
| ADRA2C | BLCA | 12 | None found | As above |
| BRCA | ||||
| ESCA | ||||
| HNSC | ||||
| LUSC | ||||
| STAD | ||||
| UCEC | ||||
| ADRB1 | ESCA | 14 | None found | |
| ADRB2 | HNSC | 15 | Propranolol suppresses pancreatic and breast cancers invasion, protects patients with skin melanoma from disease recurrence and death and avoids EGFR inhibitor resistance in lung cancer [40, 41, 76, 77] | Treatment of hypertension or irregular heart rate |
| KIRC | ||||
| KIRP | ||||
| THCA | ||||
| CNR1 | ESCA | 1 | Rimonabant inhibits human breast cancer cell proliferation [78] | Anorectic antiobesity (drug withdrawn) |
| THCA | ||||
| HTR7 | BLCA | 20 | None found | Many indications, including depression, psychosis and panic disorder |
All receptors show mean expression (RPKM) values > = 100. For Gi/o-linked GPCRs we sought only those that showed no significant fold-change when comparing tumors to wild-types (i.e., as overexpression likely indicates an oncogenic activity); for Gs-linked GPCRs we included all that were not significantly under-expressed. Cancer types in italic are those where GNAS activating mutations or Gi/o GPCR down-regulation/deactivation is observed. Agonist/antagonist classification has been derived from IUPHAR [35]. +Fingolimod (phosphorylated metabolite) is a functional antagonist for S1PR1. It first acts as an agonist, but induces degradation of S1PR1