Tocci Piera, Rosanò Laura, Bagnato Anna
Preclinical Models and New Therapeutic Agents Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Regina Elena National Cancer Institute, Rome, Italy.
Institute of Molecular Biology and Pathology, CNR, Rome, Italy.
Front Endocrinol (Lausanne). 2019 Sep 4;10:609. doi: 10.3389/fendo.2019.00609. eCollection 2019.
Recent studies imply a key role of endothelin-1 receptor (ET-1R), belonging to the largest family of G protein-coupled receptors (GPCR), in the regulation of a plethora of processes involved in tumorigenesis and metastatic progression. β-arrestin-1 (β-arr1) system has been recognized as a critical hub controlling GPCR signaling network, directing the GPCR's biological outcomes. In ovarian cancer, ET-1R/β-arr1 axis enables cancer cells to engage several integrated signaling, and represents an actionable target for developing novel therapeutic approaches. Preclinical research studies demonstrate that ET-1R blockade by the approved dual ETR/ETR antagonist macitentan counteracts β-arr1-mediated signaling network, and hampers the dialogue among cancer cells and the tumor microenvironment, interfering with metastatic progression and drug response. In light of major developments in the ET-1R signaling paradigm, this review article discusses the emerging evidence of the dual ET-1R antagonist treatment in cancer, and outlines our challenge in preclinical studies warranting the repurposing of ET-1R antagonists for the design of more effective clinical trials based on combinatorial therapies to overcome, or prevent, the onset of drug resistance.
最近的研究表明，内皮素-1受体（ET-1R）属于G蛋白偶联受体（GPCR）的最大家族，在调节肿瘤发生和转移进展所涉及的众多过程中发挥关键作用。β-抑制蛋白-1（β-arr1）系统已被认为是控制GPCR信号网络、指导GPCR生物学结果的关键枢纽。在卵巢癌中，ET-1R/β-arr1轴使癌细胞能够参与多种整合信号传导，是开发新型治疗方法的一个可行靶点。临床前研究表明，已获批的双重ETR/ETR拮抗剂马昔腾坦对ET-1R的阻断可抵消β-arr1介导的信号网络，并阻碍癌细胞与肿瘤微环境之间的相互作用，干扰转移进展和药物反应。鉴于ET-1R信号模式的重大进展，本文综述讨论了双重ET-1R拮抗剂治疗癌症的新证据，并概述了我们在临床前研究中面临的挑战，即需要重新利用ET-1R拮抗剂，以设计更有效的基于联合疗法的临床试验，以克服或预防耐药性的发生。
