GPCRs as Emerging Cancer Drug Targets: Target Validation of oGPCR, GPR161 and its Role in Triple Negative Breast Cancer
Authors: Gutierrez Ainhoa Nieto , McDonald Patricia H 
Published: June 2021

Both orphan and well‐characterized GPCRs are linked to the development and progression of cancer, and an increasing number of studies link aberrant GPCR expression and activation to numerous types of human malignancies. For example, GPCRs such as LPA, chemokines, endothelin and prostaglandin receptors play major roles in angiogenesis, metastasis and inflammation in cancer. Some orphan GPCRs (oGPCR) have also been linked to cancer development and progression on the basis of their overexpression and/or up‐regulation by diverse factors. Given the fact that GPCRs represent a major pharmaceutical target class, and the emerging roles GPCRs play in cancer pathogenesis, it is surprising that very few GPCRs have been effectively exploited in pursuit of anti‐cancer therapies.

Utilizing genomic information derived from breast cancer patients, Feigin et al (2014) discovered that the oGPCR, GPR161, is highly overexpressed specifically in triple negative breast cancer (TNBC); a subset of breast cancer with poor prognosis owing to the lack of effective targeted therapies. Moreover, retrospective data analyses revealed that patients expressing higher levels of GPR161 have an increased probability of disease relapse and worse overall survival. We aimed to generate corroborating data and validate GPR161 as a target for TNBC. Using TCGA data, patient‐derived cells, and established cell lines, we demonstrated its overexpression specifically in TNBC. By overexpression and knock‐down of the receptor in both MDA‐MB‐231 (TNBC cell line) and MCF‐10A (non‐tumorigenic breast epithelial cell line), we established a relationship between GPR161 expression levels and different aspects of cancer progression; cell growth, survival, invasion, and epithelial to mesenchymal transition (EMT) initiation.

The lack of knowledge regarding GPR161 endogenous ligands, lack of synthetic ligands, and a poor understanding of its signalling capacity hinder efforts to enable HTS campaigns and validate its potential. New assay methods have become available that are not based on G protein activation, but instead exploit the molecular mechanism underlying the attenuation of G protein signalling (desensitization) mediated by βarrestin. Despite the lack of GPR161 ligands, we have demonstrated that GPR161 has the potential to recruit βarrestin in an ‘agonist‐dependent’ manner and therefore most likely utilizes the classical mechanism of agonist‐driven βarrestin‐mediated desensitization, such that, an assay that monitors ligand‐driven βarrestin recruitment to GPR161, is relevant and can be enabled in an HTS‐compatible format.

As more work needs to be done to understand the molecular mechanisms by which GPR161 influences cancer progression which is of critical importance to exploiting its utility as an oncology drug target, we have corroborated its potential as a novel drug target for TNBC. Furthermore, we have developed a cell‐based functional assay that will facilitate the identification of GPR161 small molecule modulators that can serve as molecular probes to further interrogate its role in TNBC, and that may have the potential to be developed as novel TNBC targeted therapies.

Support or Funding Information

H Lee Moffitt Cancer Ctr

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.