Cumulative concentration of endothelin-1 and endothelin-3 in patients with acute myocardial infarction: beyond the endothelial dysfunction

Precision oncology relies on the identification of actionable vulnerabilities that can be exploited for rational combination therapies. For example, the endothelin-1 receptors (ET-1R) signaling system is shared by a broad landscape of human tumors, providing many aggressive features. As such, it represents an important vulnerability that may offer a broad window of therapeutic efficacy for the development of new treatment strategies in oncology. Accumulating data indicate that endothelins and their receptors, known as ETAR and ETBR, are pivotal cues in the regulation of tumor cells and their peculiar tumor microenvironment (TME) by controlling angiogenesis, immune response, cancer invasion, and metastatic dissemination. By the cross-talk with multiple signaling pathways mainly through the scaffold protein beta -arrestin1 (beta -arr1), ET-1R axis cooperates with an array of molecular determinants, including transcription factors and co-factors, strongly affecting tumor cell fate and behavior. In this scenario, recent findings shed light on the interplay between ET-1 and the transcriptional coactivator YAP, whose activation positively correlates with malignancy, relapse, metastasis, lower overall survival and chemoresistance, enabling phenotypic plasticity, changes in cell fates, and cell-cell communications. Recent evidence implies that ET-1R/YAP also acts as a hub by which tumor cells can reprogram their surrounding ecosystem, including fibroblasts and endothelial cells, into a resilient, growth-promoting TME. Notably, ET-1/ET-1R axis instigates a transcriptional interplay involving YAP and mutant p53 protein, which share a common gene signature and cooperate in nuclear complexes that turn on a highly selective transcriptional response as orchestrators that act on the tumor's epithelial and stromal components. Based on these evidences, we aim to demonstrate the potential of dual ET-1R antagonists in the field of oncology. ET-1R blockade by the FDA approved dual ET-1 receptor antagonist, as macitentan, interferes with ET-1R-guided signaling interplay, through the simultaneous suppression of signaling crosstalk with key oncogenic effectors, as YAP, involved in the intricate regulation of tumor and TME components,