The MAO inhibitors phenelzine and clorgyline revert enzalutamide resistance in castration resistant prostate cancer

Keliang Wang,Jun Luo,Shuyuan Yeh,Chi-Ping Huang,Wanhai Xu,Philip Chang,Chawnshang Chang,Yuanjie Niu,Yezi Zhu,Emmanuel S Antonarakis,Changxue Lu,Jialin Meng,Gonghui Li,Jie Luo,Bosen You

doi:10.1038/s41467-020-15396-5

Abstract

The antiandrogen enzalutamide (Enz) has improved survival in castration resistant prostate cancer (CRPC) patients. However, most patients eventually develop Enz resistance that may involve inducing the androgen receptor (AR) splicing variant 7 (ARv7). Here we report that high expression of monoamine oxidase-A (MAO-A) is associated with positive ARv7 detection in CRPC patients following Enz treatment. Targeting MAO-A with phenelzine or clorgyline, the FDA-approved drugs for antidepression, resensitize the Enz resistant (EnzR) cells to Enz treatment and further suppress EnzR cell growth in vitro and in vivo. Our findings suggest that Enz-increased ARv7 expression can transcriptionally enhance MAO-A expression resulting in Enz resistance via altering the hypoxia HIF-1α signals. Together, our results show that targeting the Enz/ARv7/MAO-A signaling with the antidepressants phenelzine or clorgyline can restore Enz sensitivity to suppress EnzR cell growth, which may indicate that these antidepression drugs can overcome the Enz resistance to further suppress the EnzR CRPC.

Highlights

The antiandrogen enzalutamide (Enz) has improved survival in castration resistant prostate cancer (CRPC) patients
The results revealed higher expression of monoamine oxidase-A (MAO-A) in human Prostate cancer (PCa) tissues compared to normal prostate tissues (Fig. 1b), and higher MAO-A expression in higher Gleason score tumors and recurrent PCa (Fig. 1b, Supplementary Fig. 1a)
The results revealed that while 1.5 months of Enz treatment alone could induce the development of Enz resistance by reducing Enz sensitivity from 54% to 24%.(Fig. 2l vs m), the combination of Enz and clorgyline delayed the development of Enz resistance by increasing Enz sensitivity from 54%→24% to 54%→33% or from 54%→24% to 54%→43%

Summary

Introduction

The antiandrogen enzalutamide (Enz) has improved survival in castration resistant prostate cancer (CRPC) patients. Targeting MAO-A with phenelzine or clorgyline, the FDA-approved drugs for antidepression, resensitize the Enz resistant (EnzR) cells to Enz treatment and further suppress EnzR cell growth in vitro and in vivo. Our results show that targeting the Enz/ARv7/MAO-A signaling with the antidepressants phenelzine or clorgyline can restore Enz sensitivity to suppress EnzR cell growth, which may indicate that these antidepression drugs can overcome the Enz resistance to further suppress the EnzR CRPC. Targeting MAO-A with its specific inhibitor clorgyline[26] or phenelzine[27], the existing antidepression drugs, can restore Enz sensitivity to further suppress EnzR cell growth. We provide preclinical data supporting the clinical development of these existing FDA-approved drugs for the purpose of treating mCRPC patients with elevated ARv7

Methods

Results

Conclusion