The Pharmacology and Molecular Mechanisms of ADGRF1 (GPR110) in Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer

Human epidermal growth factor receptor-2-positive (HER2+) is overexpressed in 15-20% of breast cancer (BC) patients. Despite the success of the combination regimen containing multiple anti-HER2 drugs plus chemotherapy, one-third of patients develop drug resistance and hence progressive disease eventually responsible for early mortality. On the other hand, one-third of patients with HER2+ BC have pathological complete response, a surrogate for survival, to chemotherapy-sparing anti-HER2 drug combinations that have lower toxicities. Therefore, new drug targets that improve efficacy of anti-HER2 drugs and/or chemotherapy will help to prolong survival and avoid toxicities. G protein-coupled receptors (GPCRs) are known to be excellent drug targets due to their plasma membrane localization, high specificity and target-selectivity of ligands, and availability of large GPCR-targeting chemical libraries for screening. Over 30% of the Food and Drug Administration (FDA)-approved drugs target GPCRs and are used to treat a wide-range of chronic diseases, underscoring their overall favorable long-term safety profile. Our laboratory has previously identified ADGRF1 (formerly known as GPR110), an understudied and druggable adhesion GPCR (aGPCR), to play a critical role in promoting tumorigenesis in HER2+ BC. We recently reported that ADGRF1 overexpression predicted poor survival in HER2+ BC patients. Also, ADGRF1 overexpression promoted, whereas its knockdown inhibited, the tumorigenic behavior in HER2+ BC cells. Similarly, ADGRF1-overexpressing HER2+ cells led to faster tumor initiation and growth in vivo. Conversely, when ADGRF1-overexpressing cells were injected with growth factor reduced Matrigel (1:1), the tumor formation and growth reduced dramatically. These data led us to speculate an interaction between ADGRF1 and extracellular matrix (ECM) components of Matrigel. In these studies, we aimed to (1) investigate ADGRF1 signaling pathways in mediating its effects on tumorigenesis, (2) evaluate the crosstalk of ADGRF1 with HER1/HER2 pathways and the role of STAT3 as a downstream mediator of tumorigenesis promoted by ADGRF1 signaling, and (3) identify the proteogenomic signaling network of ADGRF1, in HER2+ BC. Our studies presented here indicate a pro-tumorigenic function of ADGRF1 via coupling to Gαs and activation of STAT3 signaling. We show that ADGRF1 overexpression promotes quiescence and chemoresistance in HER2+ BC, further supporting its role in tumorigenesis. We also show that ADGRF1 switches from tumor promoting to tumor suppressive function likely upon interaction with laminin-111. ADGRF1 interaction with ECM protein(s) causes inhibition of Gαs coupling and STAT3 phosphorylation as well as increase in senescence. ADGRF1, upon interaction with ECM protein(s), also induces HER2 expression and enhances anti-HER2 drugs sensitivity in HER2+ BC. Insights into how ADGRF1 signaling is governed by laminin-111 will help to develop novel therapeutic strategies relevant to this interaction in HER2+ BC. ADGRF1 is an understudied aGPCR yet implicated in different cancers and diseases. Hence, our studies serve as the basis to explore ADGRF1 as a novel drug target in cancer and other diseases.