Targeting the Hippo Pathway in Prostate Cancer: What’s New?

Abstract

Identifying novel therapeutic targets for the treatment of prostate cancer (PC) remains a key area of research. With the emergence of resistance to androgen receptor (AR)-targeting therapies, other signalling pathways which crosstalk with AR signalling are important. Over recent years, evidence has accumulated for targeting the Hippo signalling pathway. Discovered in Drosophila melanogasta, the Hippo pathway plays a role in the regulation of organ size, proliferation, migration and invasion. In response to a variety of stimuli, including cell–cell contact, nutrients and stress, a kinase cascade is activated, which includes STK4/3 and LATS1/2 to inhibit the effector proteins YAP and its paralogue TAZ. Transcription by their partner transcription factors is inhibited by modulation of YAP/TAZ cellular localisation and protein turnover. Trnascriptional enhanced associate domain (TEAD) transcription factors are their classical transcriptional partner but other transcription factors, including the AR, have been shown to be modulated by YAP/TAZ. In PC, this pathway can be dysregulated by a number of mechanisms, making it attractive for therapeutic intervention. This review looks at each component of the pathway with a focus on findings from the last year and discusses what knowledge can be applied to the field of PC.

The regulatory networks of the Hippo signaling pathway in cancer development

“…In addition, in vitro selection of appropriate inhibitors for YAP-TEAD interaction is also a useful breakthrough point 104 , 105 . The small molecule compound Verteporfin (VP) could inhibit the YAP-TEAD interaction and show a significant inhibitory effect on TEAD transcription activity.…”

MicroRNAs in Epithelial–Mesenchymal Transition Process of Cancer: Potential Targets for Chemotherapy

“…FOXO1 was found as the direct target of miR-27a, and miR-27a could significantly inhibit FOXO1 expression as well as the Wnt pathway [ 48 ]. Prostate cancer is one of the most common cancers among men, resulting in over 11,000 deaths per year [ 49 ]. Real-time PCR results determined the overexpression of miR-19a in prostate cancer.…”

Unraveling the IGF System Interactome in Sarcomas Exploits Novel Therapeutic Options

“…Aberrant regulation of the Hippo pathway drives tumor development and several mechanisms of cancer progression, including metastasis, EMT, and resistance to anoikis [222]. Pharmacological approaches targeting YAP/TAZ in tumor cells have been recently developed [223]. The authophagy inhibitor verteporfin is a small molecule and the most widely used Hippo pathway inhibitor.…”

“…The authophagy inhibitor verteporfin is a small molecule and the most widely used Hippo pathway inhibitor. It abrogates the interaction between YAP/TAZ and TEAD, therefore affecting their transcriptional activity [222,223]. Clinical trials are currently recruiting patients to test verteporfin activity in glioblastoma (NCT04590664) and pancreatic tumors (NCT03033225).…”