TALEN-engineered AR gene rearrangements reveal endocrine uncoupling of androgen receptor in prostate cancer

Michael D. Nyquist, Yingming Li, Tae Hyun Hwang, Luke S. Manlove, Robert L. Vessella, Kevin A T Silverstein, Daniel F. Voytas, Scott M. Dehm

Research output: Contribution to journalArticle

89 Scopus citations

Abstract

Androgen receptor (AR) target genes direct development and survival of the prostate epithelial lineage, including prostate cancer (PCa). Thus, endocrine therapies that inhibit the AR ligand-binding domain (LBD) are effective in treating PCa. AR transcriptional reactivation is central to resistance, as evidenced by the efficacy of AR retargeting in castration-resistant PCa (CRPC) with next-generation endocrine therapies abiraterone and enzalutamide. However, resistance to abiraterone and enzalutamide limits this efficacy in most men, and PCa remains the second-leading cause of male cancer deaths. Here we show that AR gene rearrangements in CRPC tissues underlie a completely androgen-independent, yet AR-dependent, resistance mechanism. We discovered intragenic AR gene rearrangements in CRPC tissues, which we modeled using transcription activator-like effector nuclease (TALEN)-mediated genome engineering. This modeling revealed that these AR gene rearrangements blocked full-length AR synthesis, but promoted expression of truncated AR variant proteins lacking the AR ligand- binding domain. Furthermore, these AR variant proteins maintained the constitutive activity of the AR transcriptional program and a CRPC growth phenotype independent of full-length AR or androgens. These findings demonstrate that AR gene rearrangements are a unique resistance mechanism by which AR transcriptional activity can be uncoupled from endocrine regulation in CRPC.

Original languageEnglish (US)
Pages (from-to)17492-17497
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number43
DOIs
StatePublished - Oct 22 2013

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