Effects of Sorafenib on C-Terminally Truncated Androgen Receptor Variants in Human Prostate Cancer Cells

Zengerling, Friedemann; Streicher, Wolfgang; Schrader, Andres Jan; Schrader, Mark; Nitzsche, Bianca; Cronauer, Marcus V.; Höpfner, Michael

doi:10.3390/ijms130911530

Cited by 16 publications

(10 citation statements)

References 39 publications

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“…This property was not observed with the FL-AR, suggesting that it is restricted to the Q640Stop mutant and may be a mechanism by which it contributes to castrate resistance 31 . Consistent with the finding that Q640Stop phosphorylation is required for activity, the multikinase inhibitor sorafenib inhibited FL-AR and Q640Stop activity in castrate resistant cells 33 .…”

Section: Premature Chain Termination Generates a C-terminal Deleted Arsupporting

confidence: 79%

On the Origins of the Androgen Receptor Low Molecular Weight Species

Mudryj

Tepper

2013

HORM CANC

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Prostate cancer (CaP), a commonly diagnosed malignancy, is readily treated by androgen ablation. This treatment temporarily halts the disease, but castrate resistant neoplasms that are refractory to current therapies emerge. There are multiple mechanisms by which CaP cells circumvent androgen ablation therapies, but this review focuses on the emergence of low molecular weight androgen receptor species that are missing the ligand binding domain and function independently of ligand to drive proliferation. The etiology, biological activity, unique feature, predictive value and therapeutic implication of these androgen receptor isoforms are discussed in depth.

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Section: Premature Chain Termination Generates a C-terminal Deleted Arsupporting

confidence: 79%

On the Origins of the Androgen Receptor Low Molecular Weight Species

Mudryj

Tepper

2013

HORM CANC

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“…Would co-suppressing the two pathways lead to a more robust induction of AR-Vs and AR-V-driven tumor progression? If so, would co-targeting the Akt pathway with an agent that can induce AR-V degradation (Cao, et al 2013; Kwegyir-Afful, et al 2015; Li, et al 2012a; Liu, et al 2014a; Sun, et al 2015; Yamashita, et al 2012; Yu, et al 2014; Zengerling, et al 2012) alleviate this problem? These questions need to be carefully addressed.…”

Section: Ar-v7 Degradationmentioning

confidence: 99%

“…Various approaches have been explored to disrupt AR-V signaling, such as targeting AR N-terminal domain (Myung, et al 2013) or DNA-binding interface (Dalal, et al 2014; Li, et al 2014a), inducing AR-V protein degradation (Cao et al 2013; Kwegyir-Afful et al 2015; Li et al 2012a; Liu et al 2014a; Sun et al 2015; Yamashita et al 2012; Yu et al 2014; Zengerling et al 2012), reducing AR-V expression (Mashima, et al 2010; Zhan, et al 2013), inhibiting AR-V chromatin binding (Chan et al 2015; Li, et al 2015a), disrupting AR-FL and AR-V dimerization (Streicher, et al 2014), or using antisense oligonucleotides against exons shared by AR-FL and AR-Vs (Yamamoto et al 2015). Here, we describe several AR-V-targeting agents that have entered clinical trials for cancer treatment.…”

Section: Therapeutic Targeting Of Ar-vsmentioning

confidence: 99%

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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“…When full-length AR or AR Q640X was expressed in AR-null PC3 cells sorafenib treatment inhibited transcriptional activity of both full-length and AR Q640X via proteasomal degradation, with no effect on nuclear localization. Furthermore, sorafenib inhibited proliferation in both AR negative (DU145, PC3) and AR positive (LNCaP, 22Rv1) cells, with significantly more inhibition in AR positive cells (Zengerling, et al 2012). In further support of an important role for AR variant regulation by phosphorylation, a recent report found that DAB2IP is capable of preventing both full-length AR and AR variant nuclear localization through dual mechanisms of inhibiting c-src phosphorylation of AR S81 and PP2A-mediated S81 dephosphorylation (Wu, et al 2013).…”

Section: Introductionmentioning

confidence: 99%

Biologic and clinical significance of androgen receptor variants in castration resistant prostate cancer

Ware¹,

García-Blanco²,

Armstrong³

et al. 2014

Endocrine-Related Cancer

133

111

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As prostate cancer progresses to the lethal castration resistant and metastatic form, genetic and epigenetic adaptation, clonal selection, and evolution of the tumor microenvironment contribute to the emergence of unique biologic characteristics under the selective pressure of external stresses. These stresses include the therapies applied in the clinic or laboratory and the exposures of cancers to hormonal, paracrine, or autocrine stimuli in the context of the tumor micro- and macro-environment. The androgen receptor (AR) is a key gene involved in prostate cancer etiology and oncogenesis, including disease development, progression, response to initial hormonal therapies, and subsequent resistance to hormonal therapies. Alterations in the AR signaling pathway have been observed in certain selection contexts and contribute to the resistance to agents that target hormonal regulation of the AR, including standard androgen deprivation therapy (ADT), anti-androgens such as enzalutamide, and androgen synthesis inhibition with abiraterone acetate. One such resistance mechanism is the synthesis of constitutively active AR variants lacking the canonical ligand binding domain. This review focuses on the etiology, characterization, biologic properties, and emerging data contributing to the clinical characteristics of AR variants, and suggests approaches to full-length AR and AR variant biomarker validation, assessment, and systemic targeting in the clinic.

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Effects of Sorafenib on C-Terminally Truncated Androgen Receptor Variants in Human Prostate Cancer Cells

Cited by 16 publications

References 39 publications

On the Origins of the Androgen Receptor Low Molecular Weight Species

On the Origins of the Androgen Receptor Low Molecular Weight Species

Emerging data on androgen receptor splice variants in prostate cancer

Biologic and clinical significance of androgen receptor variants in castration resistant prostate cancer

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