Inhibition of the erythropoietin-producing receptor EPHB4 antagonizes androgen receptor overexpression and reduces enzalutamide resistance

Abstract

Prostate cancer (PCa) cells heavily rely on an active androgen receptor (AR) pathway for their survival. Enzalutamide (MDV3100) is a second-generation antiandrogenic drug that was approved by the Food and Drug Administration in 2012 to treat patients with castration-resistant prostate cancer (CRPC). However, emergence of resistance against this drug is inevitable, and it has been a major challenge to develop interventions that help manage enzalutamide-resistant CRPC. Erythropoietin-producing human hepatocellular (Eph) receptors are targeted by ephrin protein ligands and have a broad range of functions. Increasing evidence indicates that this signaling pathway plays an important role in tumorigenesis. Overexpression of EPH receptor B4 (EPHB4) has been observed in multiple types of cancer, being closely associated with proliferation, invasion, and metastasis of tumors. Here, using RNA-Seq analyses of clinical and preclinical samples, along with several biochemical and molecular methods, we report that enzalutamide-resistant PCa requires an active EPHB4 pathway that supports drug resistance of this tumor type. Using a small kinase inhibitor and RNAi-based gene silencing to disrupt EPHB4 activity, we found that these disruptions re-sensitize enzalutamide-resistant PCa to the drug both in vitro and in vivo. Mechanistically, we found that EPHB4 stimulates the AR by inducing proto-oncogene c-Myc (c-Myc) expression. Taken together, these results provide critical insight into the mechanism of enzalutamide resistance in PCa, potentially offering a therapeutic avenue for enhancing the efficacy of enzalutamide to better manage this common malignancy.

Expression of the erythropoietin receptor in patients with proliferative diabetic retinopathy and its correlation with postoperative visual prognosis

“…Specifically, after binding to EpoR on the surface of erythroid progenitor cells and proto-erythrocytes, Epo can promote cell proliferation and differentiation to form functionally mature red blood cells. Furthermore, Epo promotes capillary formation without weakening the tight junctions between endothelial cells and thus does not increase exudation (12,13). Therefore, Epo and its receptor, EpoR, have gradually attracted attention as independent factors promoting retinal neovascularization (14).…”

Mechanisms of Resistance to Second-Generation Antiandrogen Therapy for Prostate Cancer: Actual Knowledge and Perspectives

“…Another cellular pathway involved in AR activation is c-Myc. One study showed induction of c-Myc’s expression by erythropoietin-producing human hepatocellular (Eph) receptors, which is a key factor for enzalutamide resistance [ 28 ].…”

Diptoindonesin G antagonizes AR signaling and enhances the efficacy of antiandrogen therapy in prostate cancer

“…5,7,8,19 AR and AR-Vs are the most frequently aberrant genes found in the development of drug resistance, making them the first-line targets on the clinical treatment. Recently, multiple studies reveal the underlying signaling pathways involved in the acquisition of Enzalutamide resistance, such as Notch1, 41 EPHB4, 42 Wnt/β-Catenin, 43 noncanonical Wnt, 44 EZH2, 45 and HMGCR. 46 The inhibition of these pathways/molecules could significantly enhance the efficacy of Enzalutamide through cooperative repression on the AR signaling pathway, further emphasizing that targeting AR and AR-Vs is the dominant therapeutic strategy to treat prostate cancer in the clinic.…”