A Novel Small Molecular Prostaglandin Receptor EP4 Antagonist, L001, Suppresses Pancreatic Cancer Metastasis.

Jiacheng He,Xuekui Du,Hankun Zhang,Yumiao Zhao,Fanhui Meng,Wei Wang,Mingyao Liu,Ying Zhang,Xiaolei Chai,Junjie Yang,Weiwei Yu,Guichao Li,Weiqiang Lu,Yao Zhang,Xianhua Lin

doi:10.3390/molecules27041209

Abstract

Metastatic pancreatic cancer remains a major clinical challenge, emphasizing the urgent need for the exploitation of novel therapeutic approaches with superior response. In this study, we demonstrate that the aberrant activation of prostaglandin E2 (PGE2) receptor 4 (EP4) is a pro-metastatic signal in pancreatic cancer. To explore the therapeutic role of EP4 signaling, we developed a potent and selective EP4 antagonist L001 with single-nanomolar activity using a panel of cell functional assays. EP4 antagonism by L001 effectively repressed PGE2-elicited cell migration and the invasion of pancreatic cancer cells in a dose-dependent manner. Importantly, L001 alone or combined with the chemotherapy drug gemcitabine exhibited remarkably anti-metastasis activity in a pancreatic cancer hepatic metastasis model with excellent tolerability and safety. Mechanistically, EP4 blockade by L001 abrogated Yes-associated protein 1 (YAP)-driven pro-metastatic factor expression in pancreatic cancer cells. The suppression of YAP’s activity was also observed upon L001 treatment in vivo. Together, these findings support the notions that EP4–YAP signaling axis is a vital pro-metastatic pathway in pancreatic cancer and that EP4 inhibition with L001 may deliver a therapeutic benefit for patients with metastatic pancreatic cancer.

Highlights

Pancreatic cancer, one of the most lethal malignancies, is the leading cause of cancerrelated death worldwide [1]
E2 (PGE2) receptor 4 (EP4) Is Essential for prostaglandin E2 (PGE2)-Induced Pancreatic Cancer Cell Migration
The mRNA expression of Yes-associated protein 1 (YAP) as well as the YAP target genes CYR61 and CTGF was increased in EP4-overexpressing cells but decreased in EP4knockdown cells (Figure 2e,f). These findings suggest that PGE2–EP4 augmented the activation of the pro-metastatic Hippo–YAP pathway in pancreatic cancer cells

Summary

Introduction

Pancreatic cancer, one of the most lethal malignancies, is the leading cause of cancerrelated death worldwide [1]. The improvement in the survival of pancreatic cancer patients has been very slow, partly due to the fact that more than 50% patients are diagnosed with metastatic disease at first presentation [2]. The 5-year survival rate of patients with localized pancreatic cancer is up to 30%, but those with distant metastatic pancreatic cancer have less than 3% [1,3]. The chemotherapeutic agent gemcitabine is a standard first-line regimen for patients with metastatic pancreatic cancer, whereas it can only increase median survival time by less than a year [4,5]. Metastatic pancreatic cancer remains a major unresolved clinical problem, highlighting the urgent need for improved therapeutic strategies with superior efficacy and less toxicity

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