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

  • Aging (Albany NY). 2020 Sep 10;12(17):17694-17712. doi: 10.18632/aging.103917.
Changyi Lin  1 ,  Fu-Ju Chou  1 ,  Jieyang Lu  1  2 ,  Wanying Lin  1 ,  Matthew Truong  1 ,  Hao Tian  1  3 ,  Yin Sun  1 ,  Jie Luo  1 ,  Rachel Yang  1 ,  Yuanjie Niu  1  3 ,  Rosa Nadal  4 ,  Emmanuel S Antonarakis  4 ,  Carlos Cordon-Cardo  5 ,  Deepak Sahasrabudhe  1 ,  Chi-Ping Huang  6 ,  Shuyuan Yeh  1 ,  Gonghui Li  2 ,  Chawnshang Chang  1  6
Affiliations
  • 1. George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology and The Wilmot Cancer Institute, University of Rochester, Rochester, NY 14642, USA.
  • 2. Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China.
  • 3. Chawnshang Chang Sex Hormone Research Center, Tianjin Institute of Urology, Tianjin Medical University, Tianjin 300211, China.
  • 4. Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA.
  • 5. Department of Pathology, Mount Sinai School of Medicine, New York, NY 10029, USA.
  • 6. Sex Hormone Research Center, Department of Urology, China Medical University and Hospital, Taichung 404, Taiwan.
PMID: 32920545 DOI: 10.18632/aging.103917
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.

Keywords
ARv7; docetaxol; enzalutamide; prostate cancer; resistance.
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