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

Changyi Lin, Fu Ju Chou, Jieyang Lu, Wanying Lin, Matthew Truong, Hao Tian, Yin Sun, Jie Luo, Rachel Yang, Yuanjie Niu, Rosa Nadal, Emmanuel S. Antonarakis, Carlos Cordon-Cardo, Deepak Sahasrabudhe, Chi Ping Huang, Shuyuan Yeh, Gonghui Li, Chawnshang Chang

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)17694-17712
Number of pages19
JournalAging
Volume12
Issue number17
DOIs
StatePublished - Sep 2020
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by George Whipple Professorship Endowment. The manuscript preparation was done with assistance from Karen Wolf.

Publisher Copyright:
© Lin et al.

Keywords

  • ARv7
  • Docetaxol
  • Enzalutamide
  • Prostate cancer
  • Resistance

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