The high mortality of epithelial ovarian cancer (EOC) is mainly caused by 
resistance to the available therapies. In EOC, the endothelin-1 (ET-1, 
EDN1)-endothelin A receptor (ETAR, EDNRA) signaling axis regulates the 
epithelial-mesenchymal transition (EMT) and a chemoresistant phenotype. However, 
there is a paucity of knowledge about how ET-1 mediates drug resistance. Here, 
we define a novel bypass mechanism through which ETAR/β-arrestin-1 (β-arr1, 
ARRB1) links Wnt signaling to acquire chemoresistant and EMT phenotype. We found 
that ETAR/β-arr1 activity promoted nuclear complex with β-catenin and p300, 
resulting in histone acetylation, chromatin reorganization, and enhanced 
transcription of genes, such as ET-1, enhancing the network that sustains 
chemoresistance. Silencing of β-arr1 or pharmacologic treatment with the dual 
ETAR/ETBR antagonist macitentan prevented core complex formation and restored 
drug sensitivity, impairing the signaling pathways involved in cell survival, 
EMT, and invasion. In vivo macitentan treatment reduced tumor growth, 
vascularization, intravasation, and metastatic progression. The combination of 
macitentan and cisplatinum resulted in the potentiation of the cytotoxic effect, 
indicating that macitentan can enhance sensitivity to chemotherapy. 
Investigations in clinical specimens of chemoresistant EOC tissues confirmed 
increased recruitment of β-arr1 and β-catenin to ET-1 gene promoter. In these 
tissues, high expression of ETAR significantly associated with poor clinical 
outcome and chemoresistance. Collectively, our findings reveal the existence of 
a novel mechanism by which ETAR/β-arr1 signaling is integrated with the 
Wnt/β-catenin pathway to sustain chemoresistance in EOC, and they offer a solid 
rationale for clinical evaluation of macitentan in combination with chemotherapy 
to overcome chemoresistance in this setting.