Androgen receptor splice variants mediate enzalutamide resistance in castration-resistant prostate cancer cell lines

Yingming Li, Siu Chiu Chan, Lucas J. Brand, Tae Hyun Hwang, Kevin A T Silverstein, Scott M. Dehm

Research output: Contribution to journalArticle

353 Citations (Scopus)

Abstract

Persistent androgen receptor (AR) transcriptional activity underlies resistance to AR-targeted therapy and progression to lethal castration-resistant prostate cancer (CRPC). Recent success in retargeting persistent AR activity with next generation androgen/AR axis inhibitors such as enzalutamide (MDV3100) has validated AR as a master regulator during all stages of disease progression. However, resistance to next generation AR inhibitors limits therapeutic efficacy for many patients. One emerging mechanism of CRPC progression is AR gene rearrangement, promoting synthesis of constitutively active truncated AR splice variants (AR-V) that lack the AR ligand-binding domain. In this study, we show that cells with AR gene rearrangements expressing both full-length and AR-Vs are androgen independent and enzalutamide resistant. However, selective knock-down of AR-V expression inhibited androgen-independent growth and restored responsiveness to androgens and antiandrogens. In heterogeneous cell populations, AR gene rearrangements marked individual AR-V-dependent cells that were resistant to enzalutamide. Gene expression profiling following knock-down of full-length AR or AR-Vs showed that AR-Vs drive resistance to AR-targeted therapy by functioning as constitutive and independent effectors of the androgen/AR transcriptional program. Further, mitotic genes deemed previously to be unique ARV targets were found to be biphasic targets associated with a proliferative level of signaling output from either ARVs or androgen-stimulated AR. Overall, these studies highlight AR-Vs as key mediators of persistent AR signaling and resistance to the current arsenal of conventional and next generation AR-directed therapies, advancing the concept of AR-Vs as therapeutic targets in advanced disease.

Original languageEnglish (US)
Pages (from-to)483-489
Number of pages7
JournalCancer Research
Volume73
Issue number2
DOIs
StatePublished - Jan 15 2013

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Castration
Androgen Receptors
Prostatic Neoplasms
Cell Line
Androgens
MDV 3100
Gene Rearrangement

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Androgen receptor splice variants mediate enzalutamide resistance in castration-resistant prostate cancer cell lines. / Li, Yingming; Chan, Siu Chiu; Brand, Lucas J.; Hwang, Tae Hyun; Silverstein, Kevin A T; Dehm, Scott M.

In: Cancer Research, Vol. 73, No. 2, 15.01.2013, p. 483-489.

Research output: Contribution to journalArticle

Li, Yingming ; Chan, Siu Chiu ; Brand, Lucas J. ; Hwang, Tae Hyun ; Silverstein, Kevin A T ; Dehm, Scott M. / Androgen receptor splice variants mediate enzalutamide resistance in castration-resistant prostate cancer cell lines. In: Cancer Research. 2013 ; Vol. 73, No. 2. pp. 483-489.
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