Update on GNA Alterations in Cancer: Implications for Uveal Melanoma Treatment

Abstract

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 (GNAS, GNAQ or GNA11) encoding genes have been identified in a significant number of tumors. Interestingly, uveal melanoma driver mutations in GNAQ/GNA11 were identified for a decade, but their discovery did not lead to mutation-specific drug development, unlike it the case for BRAF 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.

Current molecular and clinical insights into uveal melanoma (Review)

“…As reported above, chromosomal alterations in UM mainly affect chromosomes 1,3,6 and 8, and present a meaningful prognostic relevance. As regards somatic mutations, the most commonly mutated genes that have been identified in UM patients are GNAQ, GNA11 mainly affected by specific point mutations (p.Q209P and p.Q209L, respectively) and BAP1 that is subjected to several mutations occurring in the whole gene sequence ( 88 , 171 ). Unlike cutaneous melanoma, UM does not harbor typical mutations in BRAF and NRAS genes ( 153 , 172 ).…”

“…Unlike cutaneous melanoma, UM does not harbor typical mutations in BRAF and NRAS genes ( 153 , 172 ). The GNAQ and GNA11 genes encode for the Gα11 subunits and the Gαq subunits of G proteins, respectively ( 171 ). G proteins are involved in signal transduction, controlling gene transcription and, subsequently, cell survival, growth and mortality ( 171 ).…”

“…The GNAQ and GNA11 genes encode for the Gα11 subunits and the Gαq subunits of G proteins, respectively ( 171 ). G proteins are involved in signal transduction, controlling gene transcription and, subsequently, cell survival, growth and mortality ( 171 ). GNAQ and GNA11 are located on chromosome 9 (q21.2) and chromosome 19 (p13.3), respectively ( 168 ).…”

“…GNAQ and GNA11 are located on chromosome 9 (q21.2) and chromosome 19 (p13.3), respectively ( 168 ). These genes have been considered as driver oncogenes, representing early or initiating mutations in UM ( 168 , 171 ). Oncogenic mutations of GNAQ and GNA11 genes are usually mutually exclusive and were found in up to 83% of Ums ( 173 ).…”

“…Oncogenic mutations of GNAQ and GNA11 genes are usually mutually exclusive and were found in up to 83% of Ums ( 173 ). Oncogenic mutations of these genes determine a constitutive activation of G proteins, which, in turn, affect downstream signaling ( 171 ). Several intracellular pathways are regulated by GNAQ and GNA11 genes, including the RAF/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway ( 174 ).…”