The majority of ovarian cancer (OC) patients recur with a platinum-resistant disease. OC cells activate adaptive resistance mechanisms that are only partially described. Here we show that OC cells can adapt to chemotherapy through a positive-feedback loop that favors chemoresistance. In platinum-resistant OC cells we document that the endothelin-1 (ET-1)/endothelin A receptor axis intercepts the YAP pathway. This cross-talk occurs through the LATS/RhoA/actin-dependent pathway and contributes to prevent the chemotherapy-induced apoptosis. Mechanistically, β-arrestin1 (β-arr1) and YAP form a complex shaping TEAD-dependent transcriptional activity on the promoters of YAP target genes, including EDN1, which fuels a feed-forward signaling circuit that sustains a platinum-tolerant state. The FDA approved dual ET-1 receptor antagonist macitentan in co-therapy with cisplatin sensitizes resistant cells to the platinum-based therapy, reducing their metastatic potential. Furthermore, high ETAR/YAP gene expression signature is associated with a poor platinum-response in OC patients. Collectively, our findings identify in the networking between ET-1 and YAP pathways an escape strategy from chemotherapy. ET-1 receptor blockade interferes with such adaptive network and enhances platinum-induced apoptosis, representing a promising therapeutic opportunity to restore drug sensitivity in OC patients.

大多数卵巢癌（OC）患者会复发铂耐药性疾病。OC细胞激活仅部分描述的自适应抗性机制。在这里，我们显示OC细胞可以通过有利于化学抗性的正反馈回路适应化学疗法。在耐铂的OC细胞中，我们记录了内皮素1（ET-1）/内皮素A受体轴拦截了YAP途径。这种串扰是通过LATS / RhoA /肌动蛋白依赖性途径发生的，有助于防止化学疗法诱导的细胞凋亡。从机制上讲，β-arrestin1（β-arr1）和YAP在包括EDN1在内的YAP目标基因的启动子上形成了复杂的成型TEAD依赖性转录活性，从而促进了维持铂耐受状态的前馈信号回路。FDA批准双重ET-1受体拮抗剂Macitentan与顺铂的联合疗法可使耐药细胞对铂类疗法敏感，从而降低其转移潜力。此外，在OC患者中，高ETAR / YAP基因表达特征与不良的铂反应有关。总的来说，我们的发现在ET-1和YAP途径之间的网络中确定了化学疗法的逃避策略。ET-1受体阻滞干扰这种适应性网络并增强铂诱导的细胞凋亡，代表恢复OC患者药物敏感性的有希望的治疗机会。我们的发现在ET-1和YAP途径之间的网络中确定了化学疗法的逃避策略。ET-1受体阻滞干扰了这种适应性网络并增强了铂诱导的细胞凋亡，代表了恢复OC患者药物敏感性的有前途的治疗机会。我们的发现在ET-1和YAP途径之间的网络中确定了化学疗法的逃避策略。ET-1受体阻滞干扰了这种适应性网络并增强了铂诱导的细胞凋亡，代表了恢复OC患者药物敏感性的有前途的治疗机会。