The landscape of cancer-rewired GPCR signaling axes

We explored the dysregulation of G-protein-coupled receptor (GPCR) ligand systems in cancer transcriptomics datasets to uncover new therapeutics opportunities in oncology. We derived an interaction network of receptors with ligands and their biosynthetic enzymes. Multiple GPCRs are differentially regulated together with their upstream partners across cancer subtypes and are associated to specific transcriptional programs and to patient survival patterns. The expression of both receptor-ligand (or enzymes) partners improved patient stratification, suggesting a synergistic role for the activation of GPCR networks in modulating cancer phenotypes. Remarkably, we identified many such axes across several cancer molecular subtypes, including many involving receptor-biosynthetic enzymes for neurotransmitters. We found that GPCRs from these actionable axes, including, e.g., muscarinic, adenosine, 5-hydroxytryptamine, and chemokine receptors, are the targets of multiple drugs displaying anti-growth effects in large-scale, cancer cell drug screens, which we further validated. We have made the results generated in this study freely available through a webapp (gpcrcanceraxes.bioinfolab.sns.it). [Display omitted] •Systematic analysis of GPCR extracellular network in cancer transcriptomics datasets•Multiple GPCR-ligand and biosynthetic enzymes axes are deregulated in cancer•GPCR signaling axes expression correlates with patient survival•Drug targeting of GPCR axes inhibits the growth of cancer cell lines Arora et al. provide a comprehensive computational biology analysis of GPCR extracellular networks in cancer transcriptomics datasets, which reveals signaling axes associated to patient survival. Drug targeting of GPCR axes is associated with growth inhibition of cancer cell lines, thus offering new drug repurposing opportunities in oncology.