Journal
ONCOTARGET
Volume 4, Issue 5, Pages 691-704Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.975
Keywords
Androgen receptor; variant; HSP90; HSP90 inhibitor; prostate cancer
Categories
Funding
- Prostate Cancer Foundation
- Prostate Cancer Foundation of Australia/Cancer Australia [YI 0810, YI 0412, 627229]
- Royal Adelaide Hospital Research Committee
- National Health and Medical Research Council of Australia [627185, 290456, 614296]
- Pacific NW Prostate Cancer SPORE [P50 CA97186]
- Veterans Affairs Research Program
- Prostate Cancer Foundation of Australia [2011/0452]
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available