Gpr20, a class-A orphan G protein-coupled receptor (GPCR), constitutively activates Gi proteins without ligand stimulation [3]. It is involved in regulating intracellular cAMP levels and mitogenic signaling, and may play a role in controlling cellular processes [3]. It has been associated with lipid metabolism alteration in hepatic and intestinal cells, thus having a potential key role in metabolic diseases [4].

Gpr20 is selectively expressed in gastrointestinal stromal tumors (GIST) across all treatment lines, regardless of KIT/PDGFRA genotypes [1]. An antibody-drug conjugate (ADC) targeting Gpr20, DS-6157a, exhibited GPR20 expression-dependent antitumor activity in GIST xenograft models, including those resistant to multiple tyrosine kinase inhibitors (TKIs) [1]. In a phase I study of DS-6157a in advanced GIST patients, it was well-tolerated, with some patients showing tumor shrinkage [5]. Also, in early-onset preeclampsia, Siglec-6 upregulation promotes Gpr20 expression, leading to mitochondrial dysfunction in trophoblast cells, and Gpr20 downregulation can rescue the defects caused by Siglec-6 overexpression [2].

In conclusion, Gpr20 is significant in multiple biological and disease-related processes. Its constitutive activation of Gi proteins impacts cellular signaling. In GIST, it serves as a potential non-tyrosine kinase target, and in early-onset preeclampsia, it is part of a regulatory pathway affecting trophoblast mitochondrial function. Research on Gpr20, especially through models like the use of DS-6157a in GIST xenograft models, provides insights into potential therapeutic strategies for these diseases.