The JNK inhibitor AS602801 Synergizes with Enzalutamide to Kill Prostate Cancer Cells In Vitro and In Vivo and Inhibit Androgen Receptor Expression

• Type of Material: Article
• Authors: Zhenghong Li, Emory University; Carrie Sun, Emory University; Sijia Tao, Emory University; Adeboye Osunkoya, Emory University; Rebecca Arnold, Emory University; John Petros, Emory University; Xiongbing Zu, Central South University; Carlos Moreno, Emory University
• Language: English
• Date: 2020-03-18
• Publisher: Elsevier
• Publication Version: Final Published Version
• Copyright Statement: © 2020 The Authors
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.tranon.2020.100751
• Title of Journal or Parent Work: Translational Oncology
• Volume: 13
• Issue: 4
• Grant/Funding Information: This research was funded in part by NCI U01 CA168449 and in part by the Roswell Country Club Prostate Cancer Research Award, a philanthropic award provided by the Winship Cancer Institute of Emory University through the Winship Invest$ Prostate Pilot Grant Program.; Research reported in this publication was supported in part by the Emory Integrated Genomics Core (EIGC) Shared Resource and the Cancer Tissue and Pathology Core Shared Resource of Winship Cancer Institute of Emory University and NIH/NCI under award number P30CA138292.
• Keywords: migration; JNK inhibitor AS602801; PD0325901; MEK inhibitors; androgen-sensitive LNCaP cells; GSK1120212; androgen deprivation therapy; androgen-resistant C4-2 and 22Rv1 cells; AR inhibitor enzalutamide; suppressed tumor growth; JNK; invasion; MAPK; ERK1/2 inhibitor GDC-0994
• Research Categories: Biology, Cell; Health Sciences, Oncology

Abstract

In our previous study, we observed that androgen deprivation therapy (ADT) may induce a compensatory increase in MAPK or JNK signaling. Here, we tested the effects of the MEK inhibitors PD0325901 and GSK1120212, ERK1/2 inhibitor GDC-0994, and the JNK inhibitor AS602801 alone and in combination with the AR inhibitor enzalutamide (ENZ) in androgen-sensitive LNCaP cells and androgen-resistant C4-2 and 22Rv1 cells. Enzalutamide combined with AS602801 synergistically killed LNCaP, C4-2, and 22Rv1 cells, and decreased migration and invasion of LNCaP and C4-2 cells. We studied the combination of enzalutamide with AS602801 in vivo using luciferase labeled LNCaP xenografts, and observed that combination of ENZ with AS602801 significantly suppressed tumor growth compared with either drug alone. Importantly, combination therapy resulted in dramatic loss of AR mRNA and protein. Surprisingly, mechanistic studies and Nanostring data suggest that AS602801 likely activates JNK signaling to induce apoptosis. Since AS602801 had sufficient safety and toxicity profile to advance from Phase I to Phase II in clinical trials, repurposing of this compound may represent an opportunity for rapid translation for clinical therapy of CRPC patients.