Developing new targeting strategy for androgen receptor variants in castration resistant prostate cancer

Bin Wang, U. Ging Lo, Kaijie Wu, Payal Kapur, Xiangyang Liu, Jun Huang, Wei Chen, Elizabeth Hernandez, John Santoyo, Shi Hong Ma, Rey Chen Pong, Dalin He, Yi Qiang Cheng, Jer Tsong Hsieh

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

The presence of androgen receptor variant 7 (AR-V7) variants becomes a significant hallmark of castration-resistant prostate cancer (CRPC) relapsed from hormonal therapy and is associated with poor survival of CRPC patients because of lacking a ligand-binding domain. Currently, it still lacks an effective agent to target AR-V7 or AR-Vs in general. Here, we showed that a novel class of agents (thailanstatins, TSTs and spliceostatin A analogs) can significantly suppress the expression of AR-V7 mRNA and protein but in a less extent on the full-length AR expression. Mechanistically, TST-D is able to inhibit AR-V7 gene splicing by interfering the interaction between U2AF65 and SAP155 and preventing them from binding to polypyrimidine tract located between the branch point and the 3′ splice site. In vivo, TST-D exhibits a potent tumor inhibitory effect on human CRPC xenografts leading to cell apoptosis. The machinery associated with AR gene splicing in CRPC is a potential target for drugs. Based on their potency in the suppression of AR-V7 responsible for the growth/survival of CRPC, TSTs representing a new class of anti-AR-V agents warrant further development into clinical application.

Original languageEnglish
Pages (from-to)2121-2130
Number of pages10
JournalInternational Journal of Cancer
Volume141
Issue number10
DOIs
StatePublished - 15 Nov 2017

Keywords

  • AR variants
  • CRPC
  • gene splicing
  • thailanstatin

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