Emerging mechanisms of enzalutamide resistance in prostate cancer

Claessens, Frank; Helsen, Christine; Prekovic, Stefan; Broeck, Thomas Van den; Spans, Lien; Poppel, Hendrik Van; Joniau, Steven

doi:10.1038/nrurol.2014.243

Cited by 118 publications

(108 citation statements)

References 42 publications

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“…By preventing androgen binding to AR, enzalutamide inhibits the nuclear localization and transcriptional activity of AR (39). Despite the early clinical benefits, most patients eventually developed enzalutamide resistance due to reactivation of the AR signaling pathway by various mechanisms including AR truncation and point mutations (9). Here, three different PCa cell lines were used to test whether HSP90 inhibitors (17-AAG and GA) would sensitize cells to enzalutamide treatment.…”

Section: Resultsmentioning

confidence: 99%

“…Consequently, drugs targeting AR pathway such as enzalutamide have been used for CRPC patients. Although the drug provides a substantial survival benefit, patients develop enzalutamide resistance eventually due to re-activation of AR (9). Thus, new strategies targeting the AR signaling pathway are needed to overcome enzalutamide resistance.…”

Section: Introductionmentioning

confidence: 99%

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Cotargeting HSP90 and Its Client Proteins for Treatment of Prostate Cancer

Chen

Farah

et al. 2016

Molecular Cancer Therapeutics

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Castration-resistant prostate cancer (CRPC) is the later stage of prostate cancer (PCa) when the disease has stopped responding to androgen deprivation therapy (ADT). It has been established that androgen receptor (AR) re-activation is responsible for the recurrence of PCa after ADT. Thus targeting different pathways that regulate AR stability and activity should be a promising strategy for treatment of CRPC. Heat shock proteins (HSPs) are chaperones that modify stability and activity of their client proteins. HSP90, a major player of the HSP family, regulates stabilities of many proteins, including AR and Polo-like kinase 1 (Plk1), a critical regulator of many cell cycle events. Further, HSP90 is overexpressed in different cancers, including PCa. Herein, we show that co-treatment of PCa with AR antagonist enzalutamide and HSP90 inhibitor leads to more severe cell death due to a synergistic reduction of AR protein. Interestingly, we show that overexpression of Plk1 rescued the synergistic effect and that co-targeting HSP90 and Plk1 also leads to more severe cell death. Mechanistically, we show that E3 ligase CHIP, in addition to targeting AR, is responsible for the degradation of Plk1 as well. These findings suggest that co-targeting HSP90 and some of its client proteins may be a useful strategy in treatment of CRPC.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cotargeting HSP90 and Its Client Proteins for Treatment of Prostate Cancer

Chen

Farah

et al. 2016

Molecular Cancer Therapeutics

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“…Indeed, recent clinical trials have shown that the AR antagonist MDV3100 (MDV)11 and abiraterone, an inhibitor targeting androgen synthesis12, are effective against CRPC. However, recent studies have reported that AR-Vs which lack the LBD are resistant to anti-androgen therapy including MDV and abiraterone1314151617. Since the major AR-Vs identified to date have an intact N-terminal domain and DNA-binding domain, they display constitutive activity, which underlies the persistent AR signalling in CRPC expressing these variants6181920.…”

mentioning

confidence: 99%

Ailanthone targets p23 to overcome MDV3100 resistance in castration-resistant prostate cancer

Peng

Wang

et al. 2016

Nat Commun

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Androgen receptor (AR) antagonist MDV3100 is the first therapeutic approach in treating castration-resistant prostate cancer (CRPC), but tumours frequently become drug resistant via multiple mechanisms including AR amplification and mutation. Here we identify the small molecule Ailanthone (AIL) as a potent inhibitor of both full-length AR (AR-FL) and constitutively active truncated AR splice variants (AR-Vs). AIL binds to the co-chaperone protein p23 and prevents AR's interaction with HSP90, thus resulting in the disruption of the AR-chaperone complex followed by ubiquitin/proteasome-mediated degradation of AR as well as other p23 clients including AKT and Cdk4, and downregulates AR and its target genes in PCa cell lines and orthotopic animal tumours. In addition, AIL blocks tumour growth and metastasis of CRPC. Finally, AIL possesses favourable drug-like properties such as good bioavailability, high solubility, lack of CYP inhibition and low hepatotoxicity. In general, AIL is a potential candidate for the treatment of CRPC.

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“…In addition, an understanding of the mechanisms behind abiraterone (Romanel et al 2015) and enzalutamide resistance (Claessens et al 2014), and whether this is linked to altered androgen and oestrogen metabolism, will be required before the next big step is taken towards development of endocrine therapy for prostate cancer.…”

Section: Resultsmentioning

confidence: 99%

In touch with your feminine side: how oestrogen metabolism impacts prostate cancer

Rahman

Hofland

Foster

2016

Endocrine-Related Cancer

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Prostate cancer is the primary cancer in males, with increasing global incidence rates making this malignancy a significant healthcare burden. Androgens not only promote normal prostate maturity but also influence the development and progression of prostate cancer. Intriguingly, evidence now suggests endogenous and exogenous oestrogens, in the form of phytoestrogens, may be equally as relevant as androgens in prostate cancer growth. The prostate gland has the molecular mechanisms, catalysed by steroid sulphatase (STS), to unconjugate and utilise circulating oestrogens. Furthermore, prostate tissue also expresses enzymes essential for local oestrogen metabolism, including aromatase (CYP19A1) and 3β- and 17β-hydroxysteroid dehydrogenases. Increased expression of these enzymes in malignant prostate tissue compared with normal prostate indicates that oestrogen synthesis is favoured in malignancy and thus may influence tumour progression. In contrast to previous reviews, here we comprehensively explore the epidemiological and scientific evidence on how oestrogens impact prostate cancer, particularly focusing on pre-receptor oestrogen metabolism and subsequent molecular action. We analyse how molecular mechanisms and metabolic pathways involved in androgen and oestrogen synthesis intertwine to alter prostate tissue. Furthermore, we speculate on whether oestrogen receptor status in the prostate affects progression of this malignancy.

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Emerging mechanisms of enzalutamide resistance in prostate cancer

Cited by 118 publications

References 42 publications

Cotargeting HSP90 and Its Client Proteins for Treatment of Prostate Cancer

Cotargeting HSP90 and Its Client Proteins for Treatment of Prostate Cancer

Ailanthone targets p23 to overcome MDV3100 resistance in castration-resistant prostate cancer

In touch with your feminine side: how oestrogen metabolism impacts prostate cancer

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