| Summary: | Tumorigenesis is correlated with abnormal expression and activity of G protein-coupled receptors (GPCRs) and associated G proteins. Oncogenic mutations in both GPCRs and G proteins (<i>GNAS</i>, <i>GNAQ</i> or <i>GNA11</i>) encoding genes have been identified in a significant number of tumors. Interestingly, uveal melanoma driver mutations in <i>GNAQ</i>/<i>GNA11</i> were identified for a decade, but their discovery did not lead to mutation-specific drug development, unlike it the case for <i>BRAF</i> mutations in cutaneous melanoma which saw enormous success. Moreover, new immunotherapies strategies such as immune checkpoint inhibitors have given underwhelming results. In this review, we summarize the current knowledge on cancer-associated alterations of GPCRs and G proteins and we focus on the case of uveal melanoma. Finally, we discuss the possibilities that this signaling might represent in regard to novel drug development for cancer prevention and treatment.
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