G Protein-Coupled Receptors in radioiodine-refractory thyroid cancer in the Era of Precision Medicine.

Context Radioiodine-refractory thyroid cancers have poor outcomes and limited therapeutic options, i.e tyrosine kinase inhibitors, due to transient efficacy and toxicity of treatments. Therefore, combinatorial treatments with new therapeutic approaches are needed. Many studies link G Protein-Coupled Receptors (GPCRs) to cancer cell biology. Objective To perform a specific atlas of GPCRs expression in progressive and refractory thyroid cancer to identify potential targets among GPCRs aiming at drug repositioning. Method We analyzed samples from tumor and normal thyroid tissues from 17 patients with refractory thyroid cancer (twelve papillary thyroid cancers (PTC) and five follicular thyroid cancers (FTC)). We assessed the GPCR mRNA expression using the NanoString technology with a custom panel of 371 GPCRs. The data were compared with public repositories and pharmacological databases to identify eligible drugs. The analysis of prognostic value of genes was also performed with TCGA datasets. Results With our transcriptomic analysis, 4 receptors were found down regulated in FTC (VIPR1, ADGRL2/LPHN2, ADGRA3 and ADGRV1). In PTC, 24 receptors were deregulated, seven of which identified also by bioinformatics analyses of publicly available dataset on primary thyroid cancers (VIPR1, ADORA1, GPRC5B, P2RY8, GABBR2, CYSLTR2 and LPAR5). Among all the differentially expressed genes, 22 GPCRs are the target of approved drugs and some GPCRs were also associated with prognostic factors. Conclusions For the first time, we performed GPCR mRNA expression profiling in progressive and refractory thyroid cancers. These findings provide an opportunity to identify potential therapeutic targets for drug repositioning and precision medicine in radioiodine-refractory thyroid cancer.