Second-Generation HSP90 Inhibitor Onalespib Blocks mRNA Splicing of Androgen Receptor Variant 7 in Prostate Cancer Cells

Ferraldeschi, Roberta; Welti, Jonathan; Powers, Marissa; Yuan, Wei; Smyth, Tomoko; Seed, George; Riisnaes, Ruth; Hedayat, Somaieh; Wang, Hannah; Crespo, Mateus; Rodrigues, Daniel Nava; Figueiredo, Ines; Miranda, Susana; Carreira, Suzanne; Lyons, John F.; Sharp, Swee Y.; Plymate, Stephen R.; Attard, Gerhardt; Wallis, Nicola G.; Workman, Paul; Bono, Johann S. de

doi:10.1158/0008-5472.can-15-2186

Cited by 82 publications

(75 citation statements)

References 52 publications

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“…We also found that onalespib, another type HSP90 inhibitor [31], amplified the IL-6 release induced by PGF 2α in these cells. In addition, we showed that the expression levels of IL-6 mRNA induced by PGF 2α were markedly amplified by geldanamycin and onalespib.…”

Section: Discussionmentioning

confidence: 60%

HSP90 inhibitors potentiate PGF2α-induced IL-6 synthesis via p38 MAP kinase in osteoblasts

et al. 2017

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Heat shock protein 90 (HSP90) that is ubiquitously expressed in various tissues, is recognized to be a major molecular chaperone. We have previously reported that prostaglandin F2α (PGF2α), a potent bone remodeling mediator, stimulates the synthesis of interleukin-6 (IL-6) through p44/p42 mitogen-activated protein (MAP) kinase and p38 MAP kinase in osteoblast-like MC3T3-E1 cells, and that Rho-kinase acts at a point upstream of p38 MAP kinase. In the present study, we investigated the involvement of HSP90 in the PGF2α-stimulated IL-6 synthesis and the underlying mechanism in MC3T3-E1 cells. Geldanamycin, an inhibitor of HSP90, significantly amplified both the PGF2α-stimulated IL-6 release and the mRNA expression levels. In addition, other HSP90 inhibitors, 17-allylamino-17demethoxy-geldanamycin (17-AAG) and 17-dimethylamino-ethylamino-17-demethoxy-geldanamycin (17-DMAG) and onalespib, enhanced the PGF2α-stimulated IL-6 release. Geldanamycin, 17-AAG and onalespib markedly strengthened the PGF2α-induced phosphorylation of p38 MAP kinase. Geldanamycin and 17-AAG did not affect the PGF2α-induced phosphorylation of p44/p42 MAP kinase and myosin phosphatase targeting subunit (MYPT-1), a substrate of Rho-kinase, and the protein levels of RhoA and Rho-kinase. In addition, HSP90-siRNA enhanced the PGF2α-induced phosphorylation of p38 MAP kinase. Furthermore, SB203580, an inhibitor of p38 MAP kinase, significantly suppressed the amplification by geldanamycin, 17-AAG or 17-DMAG of the PGF2α-stimulated IL-6 release. Our results strongly suggest that HSP90 negatively regulates the PGF2α-stimulated IL-6 synthesis in osteoblasts, and that the effect of HSP90 is exerted through regulating p38 MAP kinase activation.

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Section: Discussionmentioning

confidence: 60%

HSP90 inhibitors potentiate PGF2α-induced IL-6 synthesis via p38 MAP kinase in osteoblasts

et al. 2017

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“…Instead, increased AR-V7 production is due to elevated AR pre-mRNA substrates for those splicing factors (Liu et al 2014b). Furthermore, the study of Ferraldeschi et al implicated a role for the molecular chaperone, HSP90, in AR-V7 splicing (Ferraldeschi, et al 2016). HSP90 inhibition leads to the disruption of AR-V7 splicing and reduction of AR-V7 level (Ferraldeschi et al 2016).…”

Section: Ar-v Productionmentioning

confidence: 99%

“…Furthermore, the study of Ferraldeschi et al implicated a role for the molecular chaperone, HSP90, in AR-V7 splicing (Ferraldeschi, et al 2016). HSP90 inhibition leads to the disruption of AR-V7 splicing and reduction of AR-V7 level (Ferraldeschi et al 2016). Finally, another study highlighted the interplay between the noncoding RNA PCGEM1 and splicing factors in contributing to AR splicing (Zhang, et al 2016).…”

Section: Ar-v Productionmentioning

confidence: 99%

“…It does not affect the activities of AR-Vs (Shafi, et al 2013; Vanaja et al 2002). However, it has been reported to play a role in AR-V7 splicing (Ferraldeschi et al 2016). The second generation HSP90 Inhibitor Onalespib was shown to block AR-V7 mRNA splicing and reduce AR-V7 level, supporting further clinical investigation of HSP90 inhibitors against AR-V7-expressing CRPC (Ferraldeschi et al 2016).…”

Section: Therapeutic Targeting Of Ar-vsmentioning

confidence: 99%

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Emerging data on androgen receptor splice variants in prostate cancer

Cao¹,

Yang²,

Dong³

2016

Endocrine-Related Cancer

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Androgen receptor splice variants are alternatively spliced variants of androgen receptor that are C-terminally truncated and lack the canonical ligand-binding domain. Accumulating evidence has indicated a significant role of androgen receptor splice variants in mediating resistance of castration-resistant prostate cancer to current therapies and in predicting therapeutic responses. As such, there is an urgent need to target androgen receptor splicing variants for more effective treatment of castration-resistant prostate cancer. Identification of precise and critical targeting points to deactivate androgen receptor splicing variants relies on a deep understanding of how they are generated and the mechanisms of their action. In this review, we will focus on the emerging data on their generation, clinical significance, and mechanisms of action as well as the therapeutic impact of these findings.

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“…Inhibition of HSP90 with onalespib was also observed to alter AR splicing and lower the expression of AR-V7 [37]. Furthermore, Yamashita et al [38] were able to reduce CWR22Rv1 xenograft tumor growth by the addition of ASC-J9, a drug that degrades AR-V3 and full length AR.…”

Section: Mechanisms Of Resistancementioning

confidence: 99%

Adaptive pathways and emerging strategies overcoming treatment resistance in castration resistant prostate cancer

Armstrong

Gao

2016

Asian Journal of Urology

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The therapies available for prostate cancer patients whom progress from hormone-sensitive to castration resistant prostate cancer include both systemic drugs, including docetaxel and cabazitaxel, and drugs that inhibit androgen signaling such as enzalutamide and abiraterone. Unfortunately, it is estimated that up to 30% of patients have primary resistance to these treatments and over time even those who initially respond to therapy will eventually develop resistance and their disease will continue to progress regardless of the presence of the drug. Determining the mechanisms involved in the development of resistance to these therapies has been the area of intense study and several adaptive pathways have been uncovered. Androgen receptor (AR) mutations, expression of AR-V7 (or other constitutively active androgen receptor variants), intracrine androgen production and overexpression of androgen synthesis enzymes such as Aldo-Keto Reductase Family 1, Member C3 (AKR1C3) are among the many mechanisms associated with resistance to anti-androgens. In regards to the taxanes, one of the key contributors to drug resistance is increased drug efflux through ATP Binding Cassette Subfamily B Member 1 (ABCB1). Targeting these resistance mechanisms using different strategies has led to various levels of success in overcoming resistance to current therapies. For instance, targeting AR-V7 with niclosamide or AKR1C3 with indomethacin can improve enzalutamide and abiraterone treatment. ABCB1 transport activity can be inhibited by the dietary constituent apigenin and antiandrogens such as bicalutamide which in turn improves response to docetaxel. A more thorough understanding of how drug resistance develops will lead to improved treatment strategies. This review will cover the current knowledge of resistance mechanisms to castration resistant prostate cancer therapies and methods that have been identified which may improve treatment response.

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Second-Generation HSP90 Inhibitor Onalespib Blocks mRNA Splicing of Androgen Receptor Variant 7 in Prostate Cancer Cells

Cited by 82 publications

References 52 publications

HSP90 inhibitors potentiate PGF2α-induced IL-6 synthesis via p38 MAP kinase in osteoblasts

HSP90 inhibitors potentiate PGF2α-induced IL-6 synthesis via p38 MAP kinase in osteoblasts

Emerging data on androgen receptor splice variants in prostate cancer

Adaptive pathways and emerging strategies overcoming treatment resistance in castration resistant prostate cancer

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