Research Papers:

A novel nonsense mutation in androgen receptor confers resistance to CYP17 inhibitor treatment in prostate cancer

Dong Han _, Shuai Gao, Kevin Valencia, Jude Owiredu, Wanting Han, Eric de Waal, Jill A. Macoska and Changmeng Cai

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Oncotarget. 2017; 8:6796-6808. https://doi.org/10.18632/oncotarget.14296

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Dong Han1, Shuai Gao1,2, Kevin Valencia1, Jude Owiredu1, Wanting Han1, Eric de Waal3, Jill A. Macoska1, Changmeng Cai1,2

1Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, Massachusetts 02125, USA

2Hematology-Oncology Division and Cancer Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA

3Biology Department, University of Suffolk, Boston, Massachusetts 02108, USA

Correspondence to:

Changmeng Cai, email: [email protected]

Keywords: prostate cancer, androgen receptor, androgen receptor mutation, CYP17 inhibitor, abiraterone

Received: September 14, 2016    Accepted: December 13, 2016    Published: December 27, 2016


The standard treatment for prostate cancer (PCa) is androgen deprivation therapy (ADT) that blocks transcriptional activity of androgen receptor (AR). However, ADT invariably leads to the development of castration-resistant PCa (CRPC) with restored activity of AR. CRPC can be further treated with CYP17 inhibitors to block androgen synthesis pathways, but most patients still relapse after a year of such treatment. The mechanisms that drive this progression are not fully understood, but AR activity, at least in a subset of cancers, appears to be restored again. Importantly, AR mutations are more frequently detected in this type of cancer. By analyzing tumor biopsy mRNA from CRPC patients who had developed resistance to CYP17 inhibitor treatment, we have identified a novel nonsense mutation (Q784*) at the ligand binding domain (LBD) of AR, which produces a C-terminal truncated AR protein that lacks intact LBD. This AR-Q784* mutant is transcriptionally inactive, but it is constitutively expressed in the nucleus and can bind to DNA in the absence of androgen. Significantly, our results show that AR-Q784* can heterodimerize with, and enhance the transcriptional activity of, full-length AR. Moreover, expressing AR-Q784* in an AR positive PCa cell line enhances the chromatin binding of endogenous AR and the recruitment of p300 coactivator under the low androgen condition, leading to increased cell growth. This activity of AR-Q784* mimics the function of some AR splice variants, indicating that CYP17 inhibitor treatment in CRPC may select for LBD-truncated forms of AR to restore AR signaling.

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