Targeting endothelin-1 receptor/β-arrestin1 network for the treatment of ovarian cancer

ABSTRACT

Introduction: Endothelin-1 receptor (ET-1R)/β-arrestin1 (β-arr1) signaling is dysregulated in ovarian cancer. This signaling circuit enables cancer cells to engage several signaling and transcriptional networks that are pervasively intertwined, and represent a potential therapeutic target for developing novel agents for ovarian cancer treatment.

Areas covered: In this article, we discuss the role of the signaling network between ET-1R and key pathways mediated by the scaffold protein β-arr1, as part of signaling complex, or as a transcription co-activator, promoting precise control of transcription of different genes, including ET-1. Therefore ET-1R/β-arr1 is an actionable node involved in the activation of a persistent feedback loop that contributes to bypass signaling. Targeting ET-1R empowering this circuit can represent a necessary measure to reach clinical efficacy. Preclinical studies demonstrate that blocking ET-1R by FDA approved dual ET_AR/ET_BR antagonist prevents β-arr1 network formation, offering a novel therapeutic strategy in ovarian cancer patients.

Expert opinion: The information provided in this review about the ET-1R/β-arr1 hub represents an invaluable tool for both identifying the interconnected pathways involved in ovarian cancer and targeting them more effectively. The new perspective arising from ET-1R therapeutics will likely prompt a valuable frame for the design of new promising combinatorial therapy, blocking compensatory networks.

KEYWORDS:

• Endothelin-1
• β-arrestin-1
• ovarian cancer
• ET-1 receptors
• therapeutic target
• ET-1 receptor antagonist

Article highlights

• ET-1R, expressed on both tumor and micrenvironmental compartments, are important for regulation of essential processes, such as cell proliferation, survival, epithelial-to-mesenchymal transition, neovascularization, response of immune cells and drug resistance.

• ET-1R have emerged as key targets and potential biomarkers in ovarian cancer.

• An intricate network of crosstalk between ET-1R signalling and other key pathways is mediated by β-arr1, acting as a signal transducer or as co-transcription factor.

• Autocrine ET-1R/β-arr1 circuit checks ovarian cell features to become invasive and less responsive to the antineoplastic drugs.

• Targeting ET-1R/β-arr1 network by non-selective ET-1R antagonists inhibits tumour progression and sensitizes to chemotherapy by hampering crucial signaling networks in both the tumor microenvironment and the tumor cells, and can be exploited in ovarian cancer patients in combinatorial approaches.

This box summarizes key points contained in the article.

Acknowledgments

We gratefully acknowledge Aldo Lupo for excellent technical assistance, Maria Vincenza Sarcone for secretarial assistance.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This work was supported by Associazione Italiana Ricerca sul Cancro (AIRC); (AIRC 18382 to A. Bagnato and AIRC 16965 to L. Rossano).