Pan-Cancer Analysis of G Protein-Coupled Receptors as Cancer Driver Genes and Drug Repurposing Targets

G protein-coupled
receptors (GPCRs), the largest family of currently
approved drug targets, are rarely targeted for cancer therapy. There
is limited research on the role of GPCRs in pan-cancer, particularly
regarding the underlying causes of their abnormal expression. The
abnormal expression of GPCRs in tumors has generally been attributed
to mutations and promoter methylation. However, transcriptional regulatory
elements of GPCRs, such as G-quadruplexes (G4s), superenhancers (SEs),
and mRNA structure, remain poorly understood. Then, these regulatory
elements were explored by utilizing PRECOG, ROSE, and ViennaRNA algorithms.
Meanwhile, cancer prognosis-related GPCRs were found based on different
expression analyses and Cox regression. A total of 326 differentially
expressed GPCRs were then identified, with 3,151 significant HR (hazard
ratios) records in pan-cancer. Notably, most cancer prognosis-related
GPCRs are coupled with Gi (GNAI1, GNAI2, and GNAI3) and Gq/11 signaling
pathways. Moreover, G4s, SEs, and mRNA structure could be utilized
to explain some of the abnormal expression for cancer prognosis-related
GPCRs. Additionally, some of these GPCRs have known drug targets such
as GCGR, CXCR4, GPR55, and so on. For an example of drug repurposing,
four drugs (i.e., theophyline, caffeine, enprofylline, and flavone)
were found that could be combined with immunotherapy for PAAD therapy
patients. Finally, we developed GPCR-PCA (G protein-coupled receptors
in pan-cancer), a web-based tool that provides fast, customizable
queries based on our GPCR-related cancer analysis to facilitate clinical
research targeting GPCRs. GPCR-PCA is available at http://gpcrpca.lsbz.store/