Cotargeting Androgen Receptor and Clusterin Delays Castrate-Resistant Prostate Cancer Progression by Inhibiting Adaptive Stress Response and AR Stability
Open Access
- 13 August 2013
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 73 (16), 5206-5217
- https://doi.org/10.1158/0008-5472.can-13-0359
Abstract
Although androgen receptor (AR) pathway inhibitors prolong survival in castrate-resistant prostate cancer (CRPC), resistance rapidly develops and is often associated with increased stress-activated molecular chaperones like clusterin (CLU) and continued AR signaling. Because adaptive pathways activated by treatment facilitate development of acquired resistance, cotargeting the stress response, activated by AR inhibition and mediated through CLU, may create conditional lethality and improve outcomes. Here, we report that CLU is induced by AR antagonism and silencing using MDV3100 and antisense, respectively, to become highly expressed in castrate- and MDV3100-resistant tumors and cell lines. CLU, as well as AKT and mitogen-activated protein kinase (MAPK) signalosomes, increase in response to MDV3100-induced stress. Mechanistically, this stress response is coordinated by a feed-forward loop involving p90rsk (RPS6KA)-mediated phosphoactivation of YB-1 with subsequent induction of CLU. CLU inhibition repressed MDV3100-induced activation of AKT and MAPK pathways. In addition, when combined with MDV3100, CLU knockdown accelerated AR degradation and repressed AR transcriptional activity through mechanisms involving decreased YB-1–regulated expression of the AR cochaperone, FKBP52. Cotargeting the AR (with MDV3100) and CLU (with OGX-011) synergistically enhanced apoptotic rates over that seen with MDV3100 or OGX-011 monotherapy and delayed CRPC LNCaP tumor and prostate-specific antigen (PSA) progression in vivo. These data indicate that cotargeting adaptive stress pathways activated by AR pathway inhibitors, and mediated through CLU, creates conditional lethality and provides mechanistic and preclinical proof-of-principle to guide biologically rational combinatorial clinical trial design. Cancer Res; 73(16); 5206–17. ©2013 AACR.Keywords
Other Versions
This publication has 44 references indexed in Scilit:
- Abiraterone and Increased Survival in Metastatic Prostate CancerThe New England Journal of Medicine, 2011
- Reciprocal Feedback Regulation of PI3K and Androgen Receptor Signaling in PTEN-Deficient Prostate CancerCancer Cell, 2011
- Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1–2 studyThe Lancet, 2010
- Targeting the Cytoprotective Chaperone, Clusterin, for Treatment of Advanced CancerClinical Cancer Research, 2010
- Development of a Second-Generation Antiandrogen for Treatment of Advanced Prostate CancerScience, 2009
- A Novel Androgen Receptor Splice Variant Is Up-regulated during Prostate Cancer Progression and Promotes Androgen Depletion–Resistant GrowthCancer Research, 2009
- Androgen deprivation therapy: progress in understanding mechanisms of resistance and optimizing androgen depletionNature Reviews Endocrinology, 2009
- Splicing of a Novel Androgen Receptor Exon Generates a Constitutively Active Androgen Receptor that Mediates Prostate Cancer Therapy ResistanceCancer Research, 2008
- Clusterin inhibits apoptosis by interacting with activated BaxNature, 2005
- Molecular determinants of resistance to antiandrogen therapyNature Medicine, 2003