The limited clinical response to platinum-based therapeutics observed in high-grade serous ovarian cancer (HG-SOC), characterized by high frequency of recurrence and TP53 mutations, might be related to oncogenic pathway network. The activation of endothelin-1 (ET-1)/endothelin A receptor (ETAR) signaling, through the ability of the scaffold protein β-arrestin1 (β-arr1) to interact with a broad repertoire of signaling proteins, integrates several pathways involved in a plethora of tumor functions. Here, we show that the Hippo effector Yes-associated protein (YAP) works as crucial signal transducer to mediate ETAR/β-arr1 signaling during HG-SOC growth, metastasis and platinum response. In patient-derived HG-SOC cells and platinum sensitive and resistant OC cell lines, we demonstrate that ET-1R activation promotes YAP and TAZ de-phosphorylation and to a greater extent in platinum-resistant OC cells. Of note, ET-1R through β-arr1, engaging a physical interaction with the novel partner YAP, triggers its cytoplasmic-nuclear shuttling. In parallel, β-arr1 mediates the ET-1R-induced Trio/RhoA/actin cytoskeleton-dependent YAP nuclear accumulation. Mechanistically, downstream of ETAR signaling, nuclear β-arr1 and YAP bind mutant p53 (mutp53), forming a competent transcriptional complex consisting of β-arr1/YAP/mutp53/TEAD. This leads to the aberrant transcriptional activation of YAP/TEAD target genes, including EDN1 (ET-1 gene), thereby fueling a feed-forward loop that ensures persistent signals sustaining aggressive traits. ET-1R inactivation, by using the dual ET-1R antagonist macitentan, shuts down β-arr1-mediated YAP/mutp53/TEAD transcriptional program, reduces tumor growth, metastatic dissemination and enhances the sensitivity to chemotherapy in the clinical model of patient-derived HG-SOC xenografts (PDX). Of clinical relevance, the combined expression of ETAR/β-arr1/YAP gene signature correlates with a worst prognosis in HG-SOC patients, carrying TP53 mutations. Altogether, these findings identify YAP as a central mediator of ETAR/β-arr1 signaling, thereby providing mechanistic and therapeutic insights to the targeting of the ETAR/β-arr1/YAP/mutp53 complex warranting the repurposing of macitentan for combinatorial treatment of HG-SOC
