Oncotarget

Research Papers:

Constitutively-active androgen receptor variants function independently of the HSP90 chaperone but do not confer resistance to HSP90 inhibitors

Joanna L Gillis, Luke A Selth, Margaret M Centenera, Scott L Townley, Shihua Sun, Stephen R Plymate, Wayne D Tilley and Lisa M Butler _

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Oncotarget. 2013; 4:691-704. https://doi.org/10.18632/oncotarget.975

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Abstract

Joanna L. Gillis1,*, Luke A. Selth1,*, Margaret M. Centenera1, Scott L. Townley1, Shihua Sun2, Stephen R. Plymate2,3,4, Wayne D. Tilley1 and Lisa M. Butler1

1 Dame Roma Mitchell Cancer Research Laboratories and Adelaide Prostate Cancer Research Centre, University of Adelaide and Hanson Institute, Adelaide, South Australia, Australia.

2 Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA.

3 Department of Urology, University of Washington School of Medicine, Seattle, Washington, USA.

4 Geriatric Research, Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA.

* These authors contributed equally to this work.

Correspondence:

Lisa M. Butler, email:

Keywords: Androgen receptor, variant, HSP90, HSP90 inhibitor, prostate cancer

Received: April 16, 2013 Accepted: April 23, 2013 Published: April 25, 2013

Abstract

The development of lethal, castration resistant prostate cancer is associated with adaptive changes to the androgen receptor (AR), including the emergence of mutant receptors and truncated, constitutively active AR variants. AR relies on the molecular chaperone HSP90 for its function in both normal and malignant prostate cells, but the requirement for HSP90 in environments with aberrant AR expression is largely unknown. Here, we investigated the efficacy of three HSP90 inhibitors, 17-AAG, HSP990 and AUY922, against clinically-relevant AR missense mutants and truncated variants. HSP90 inhibition effectively suppressed the signaling of wild-type AR and all AR missense mutants tested. By contrast, two truncated AR variants, AR-V7 and ARv567es, exhibited marked resistance to HSP90 inhibitors. Supporting this observation, nuclear localization of the truncated AR variants was not affected by HSP90 inhibition and AR variant:HSP90 complexes could not be detected in prostate cancer cells. Interestingly, HSP90 inhibition resulted in accumulation of AR-V7 and ARv567es in both cell lines and human tumor explants. Despite the apparent independence of AR variants from HSP90 and their treatment-associated induction, the growth of cell lines with endogenous or enforced expression of AR-V7 or ARv567es remained highly sensitive to AUY922. This study demonstrates that functional AR variant signaling does not confer resistance to HSP90 inhibition, yields insight into the interaction between AR and HSP90 and provides further impetus for the clinical application of HSP90 inhibitors in advanced prostate cancer.


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