Aging
Navigate
Research Paper|Volume 12, Issue 17|pp 17694—17712

Preclinical studies show using enzalutamide is less effective in docetaxel-pretreated than in docetaxel-naïve prostate cancer cells

Changyi Lin1, Fu-Ju Chou1, Jieyang Lu1,2, Wanying Lin1, Matthew Truong1, Hao Tian1,3, Yin Sun1, Jie Luo1, Rachel Yang1, Yuanjie Niu1,3, Rosa Nadal4, Emmanuel S. Antonarakis4, Carlos Cordon-Cardo5, Deepak Sahasrabudhe1, Chi-Ping Huang6, Shuyuan Yeh1, Gonghui Li2, Chawnshang Chang1,6
  • 1George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology and The Wilmot Cancer Institute, University of Rochester, Rochester, NY 14642, USA
  • 2Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China
  • 3Chawnshang Chang Sex Hormone Research Center, Tianjin Institute of Urology, Tianjin Medical University, Tianjin 300211, China
  • 4Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA
  • 5Department of Pathology, Mount Sinai School of Medicine, New York, NY 10029, USA
  • 6Sex Hormone Research Center, Department of Urology, China Medical University and Hospital, Taichung 404, Taiwan
* Equal contribution
Received: February 6, 2020Accepted: July 25, 2020Published: September 10, 2020

Copyright: © 2020 Lin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Anti-androgen therapy with Enzalutamide (Enz) has been used as a therapy for castration resistant prostate cancer (CRPC) patients after development of resistance to chemotherapy with Docetaxel (Doc). The potential impacts of Doc-chemotherapy on the subsequent Enz treatment, however, remain unclear. Here we found the overall survival rate of patients that received Enz was significantly less in patients that received prior Doc-chemotherapy than those who had not. In vitro studies from 3 established Doc resistant CRPC (DocRPC) cell lines are consistent with the clinical findings showing DocRPC patients had decreased Enz-sensitivity as well as accelerated development of Enz-resistance via enhanced androgen receptor (AR) splicing variant 7 (ARv7) expression. Mechanism dissection found that Doc treatment might increase the generation of ARv7 via altering the MALAT1-SF2 RNA splicing complex. Preclinical studies using in vivo mouse models and in vitro cell lines proved that targeting the MALAT1/SF2/ARv7 axis with small molecules, including siMALAT1, shSF2, and shARv7 or ARv7 degradation enhancers: Cisplatin or ASC-J9®, can restore/increase the Enz sensitivity to further suppress DocRPC cell growth. Therefore, combined therapy of Doc-chemotherapy with anti-ARv7 therapy, including Cisplatin or ASC-J9®, may be developed to increase the efficacy of Enz to further suppress DocRPC in patients.