Constitutively Active AR-V7 Plays an Essential Role in the Development and Progression of Castration-Resistant Prostate Cancer

Qu, Yuanyuan; Dai, Bo; Ye, Dingwei; Kong, Yunyi; Chang, Kun; Jia, Zhongwei; Yang, Xiaoqun; Zhang, Ye; Zhu, Yao; Shi, Guohai

doi:10.1038/srep07654

Cited by 156 publications

(167 citation statements)

References 29 publications

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“…Although only FL-AR was detectable at the protein level in VCaP cells, expression of the mRNA encoding both FL-AR and the AR-V7 could be measured readily. AR-V7 is the best studied of the transcriptionally active AR splice variants detected in the clinic and has been hypothesized to play a role in acquired resistance to enzalutamide and abiraterone (6,11,12,(32)(33)(34). We observed downregulation of both FL-AR and AR-V7 mRNA upon treatment with 10 nM ARV-771 in VCaP cells (Fig.…”

Section: Arv-771 Treatment Of Crpc Cells Results In Apoptosismentioning

confidence: 60%

PROTAC-induced BET protein degradation as a therapy for castration-resistant prostate cancer

Raina

Lü

Qian

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

686

654

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Prostate cancer has the second highest incidence among cancers in men worldwide and is the second leading cause of cancer deaths of men in the United States. Although androgen deprivation can initially lead to remission, the disease often progresses to castration-resistant prostate cancer (CRPC), which is still reliant on androgen receptor (AR) signaling and is associated with a poor prognosis. Some success against CRPC has been achieved by drugs that target AR signaling, but secondary resistance invariably emerges, and new therapies are urgently needed. Recently, inhibitors of bromodomain and extraterminal (BET) family proteins have shown growth-inhibitory activity in preclinical models of CRPC. Here, we demonstrate that ARV-771, a small-molecule pan-BET degrader based on proteolysis-targeting chimera (PROTAC) technology, demonstrates dramatically improved efficacy in cellular models of CRPC as compared with BET inhibition. Unlike BET inhibitors, ARV-771 results in suppression of both AR signaling and AR levels and leads to tumor regression in a CRPC mouse xenograft model. This study is, to our knowledge, the first to demonstrate efficacy with a small-molecule BET degrader in a solid-tumor malignancy and potentially represents an important therapeutic advance in the treatment of CRPC.BET | BRD4 | protein degradation | prostate | PROTAC

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Section: Arv-771 Treatment Of Crpc Cells Results In Apoptosismentioning

confidence: 60%

PROTAC-induced BET protein degradation as a therapy for castration-resistant prostate cancer

Raina

Lü

Qian

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

686

654

View full text Add to dashboard Cite

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“…These drugs significantly prolonged the survival of patients, especially those with metastatic CRPCs (34). However, CRPCs with a certain type of mutation, tandem duplication of AR exon 3 (AR-V7), which encodes a variant protein lacking the ligand-binding domain and is active in a hormone-independent manner, are still resistant to these drugs (35,36). This mutation is one of the most abundant variants found in prostate cancer cell lines including 22Rv1 and VCaP cell lines (35,37).…”

Section: Discussionmentioning

confidence: 99%

Histone Deacetylase Inhibition in Prostate Cancer Triggers miR-320–Mediated Suppression of the Androgen Receptor

et al. 2016

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Targeting androgen receptor (AR) by pharmacologic intervention is one of the effective approaches for treatment of malignant prostate cancers. Histone deacetylase (HDAC) alters the epigenetic status of tumor-associated genes, including those for miRNAs (miRNA), and affects the behavior of cancers. Here, we examined the molecular effects of a HDAC inhibitor, OBP-801, on AR expression and tumor cell growth in prostate cancers. Treatment with OBP-801 efficiently suppressed cell growth of three prostate cancer lines (22Rv1, VCaP, and LNCaP), together with AR downregulation, regardless of their hormone sensitivity. Intriguingly, this effect by OBP-801 was not due to decreased transcriptional activity of the AR gene, but due to posttranscriptional regulation, namely by miRNA-mediated suppression. Among the upregulated miRNAs after OBP-801 treatment in the three prostate cancer cell lines, miR-320a, whose expression was significantly correlated with prognosis of prostate cancers (P ¼ 0.0185), was the most closely associated with AR expression. An miR-320a mimic suppressed AR protein expression together with growth suppression, while anti-miR-320a oligonucleotide significantly abrogated the growth suppression by OBP-801 treatment. FISH analysis revealed that miR-320a was highly expressed in human normal prostate luminal cells, but was rarely expressed in prostate cancer cells. In an AR-dependent prostate tumorigenic rat model, OBP-801 treatment profoundly increased miR-320a expression and repressed prostate tumorigenesis. Our data demonstrated that OBP-801 effectively suppressed AR activity via epigenetic upregulation of miR-320a, which resulted in tumor cell growth suppression of prostate cancers. OBP-801 may be a potent AR-targeting therapeutic reagent in AR-positive prostate cancer regardless of androgen dependency. Cancer Res; 76(14); 4192-204. Ó2016 AACR.

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“…AR-V7 is an alternatively spliced isoform of the AR gene that contains the DNA-binding domain but lacks the regulatory ligand-binding domain, leading to constitutive activation of oncogenic signaling and cell proliferation. 11,12 …”

Section: Introductionmentioning

confidence: 99%

Assessment of the Validity of Nuclear-Localized Androgen Receptor Splice Variant 7 in Circulating Tumor Cells as a Predictive Biomarker for Castration-Resistant Prostate Cancer

et al. 2018

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Importance A blood test to determine whether to treat patients with metastatic castration-resistant prostate cancer (mCRPC) with an androgen receptor signaling (ARS) inhibitor or taxane is an unmet medical need. Objective To determine whether a validated assay for androgen receptor splice variant 7 (AR-V7) protein in circulating tumor cells (CTCs) that is localized to the nucleus can predict differential overall survival (OS) in mCRPC patients treated with taxanes vs. ARS inhibitors. Design Blinded correlative study. Patients were followed up to 4.3 years. Setting Multi-institution outpatient clinics at Memorial Sloan Kettering Cancer Center (USA), Institute for Cancer Research (UK) and London Health Sciences Centre (Canada). Participants A cross-sectional cohort of 248 patients with mCRPC drawn prior to 286 drug exposures were considered. The analysis subset included 142 patients drawn prior to administration of ARS inhibitors or taxanes at the second or greater line of systemic therapy for progressing mCRPC. Main Outcome(s) and Measure(s) OS following an ARS inhibitor or taxane in relation to pretherapy AR-V7 status. Results For mCRPC patients designated as high-risk by conventional prognostic factors, AR-V7-positive patients treated with taxanes have superior OS relative to those treated with ARS inhibitors, and AR-V7-negative patients treated with ARS inhibitors have superior OS relative to taxane-treated patients. Conclusion and Relevance Nuclear-localized AR-V7 protein in CTCs can identify patients who may live longer on taxane chemotherapy than on ARS inhibitors (abiraterone, enzalutamide, apalutamide).

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Constitutively Active AR-V7 Plays an Essential Role in the Development and Progression of Castration-Resistant Prostate Cancer

Cited by 156 publications

References 29 publications

PROTAC-induced BET protein degradation as a therapy for castration-resistant prostate cancer

PROTAC-induced BET protein degradation as a therapy for castration-resistant prostate cancer

Histone Deacetylase Inhibition in Prostate Cancer Triggers miR-320–Mediated Suppression of the Androgen Receptor

Assessment of the Validity of Nuclear-Localized Androgen Receptor Splice Variant 7 in Circulating Tumor Cells as a Predictive Biomarker for Castration-Resistant Prostate Cancer

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