Development and exploitation of a novel mutant androgen receptor modelling strategy to identify new targets for advanced prostate cancer therapy

O’Neill, Daniel; Jones, Dominic; Wade, Mark; Grey, James; Nakjang, Sirintra; W, Guo; Cork, David M W; Davies, Barry R.; Wedge, Steve; Robson, Craig; Gaughan, Luke

doi:10.18632/oncotarget.4347

Cited by 27 publications

(27 citation statements)

References 40 publications

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“…Darolutamide also exhibited strong antagonism for several AR mutants for which other antagonists had only reduced activity. A prime example is the AR W742C/L forms which are stimulated by bicalutamide, thus activating an androgenic gene expression program resembling that of an AR agonist . Here we show that darolutamide remained a strong antagonist whereas enzalutamide and apalutamide had only reduced antagonist properties for these AR mutants.…”

Section: Discussionmentioning

confidence: 68%

Darolutamide is a potent androgen receptor antagonist with strong efficacy in prostate cancer models

Sugawara

Baumgart

Nevedomskaya

et al. 2019

Intl Journal of Cancer

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Darolutamide is a novel androgen receptor (AR) antagonist with a distinct chemical structure compared to other AR antagonists and currently in clinical Phase 3 trials for prostate cancer. Using cell‐based transactivation assays, we demonstrate that darolutamide, its diastereomers and its main metabolite keto‐darolutamide are strong, competitive antagonists for AR wild type, and also for several mutants identified in prostate cancer patients for which other AR antagonists show reduced antagonism or even agonism. Darolutamide, its two diastereomers and main metabolite are also strong antagonists in assays measuring AR N/C interaction and homodimerization. Molecular modeling suggests that the flexibility of darolutamide allows accommodation in the W742C/L mutated AR ligand‐binding pocket while for enzalutamide the loss of the important hydrophobic interaction with W742 leads to reduced AR interaction. This correlates with an antagonistic pattern profile of coregulator recruitment for darolutamide. In vitro efficacy studies performed with androgen‐dependent prostate cancer cell lines show that darolutamide strongly reduces cell viability and potently inhibits spheroid formation. Also, a marked down‐regulation of androgen target genes paralleled by decreased AR binding to gene regulatory regions is seen. In vivo studies reveal that oral dosing of darolutamide markedly reduces growth of the LAPC‐4 cell line‐derived xenograft and of the KuCaP‐1 patient‐derived xenograft. Altogether, these results substantiate a unique antagonistic profile of darolutamide and support further development as a prostate cancer drug.

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Section: Discussionmentioning

confidence: 68%

Darolutamide is a potent androgen receptor antagonist with strong efficacy in prostate cancer models

Sugawara

Baumgart

Nevedomskaya

et al. 2019

Intl Journal of Cancer

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“…In addition, we found the AR binding motifs sequence in HCC cells were a bit different from the canonical types, and it could be attributed to the binding motif variants or tissue specificity [33, 34], which need further study. Moreover, we noticed that under the androgen stimulating, the Nanog Neg cells could turn to be Nanog Pos .…”

Section: Discussionmentioning

confidence: 99%

Androgen/androgen receptor axis maintains and promotes cancer cell stemness through direct activation of Nanog transcription in hepatocellular carcinoma

et al. 2016

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Hepatocellular carcinoma (HCC) is one of the most common and malignant cancers. The HCC incidence gets a strong sexual dimorphism as men are the major sufferers in this disaster. Although several studies have uncovered the presentative correlation between the axis of androgen/androgen receptor (AR) and HCC incidence, the mechanism is still largely unknown. Cancer stem cells (CSCs) are a small subgroup of cancer cells contributing to multiple tumors malignant behaviors, which play an important role in oncogenesis of various cancers including HCC. However, whether androgen/AR axis involves in regulation of HCC cells stemness remains unclear. Our previous study had identified that the pluripotency factor Nanog is not only a stemness biomarker, but also a potent regulator of CSCs in HCC. In this study, we revealed androgen/AR axis can promote HCC cells stemness by transcriptional activation of Nanog expression through directly binding to its promoter. In HCC tissues, we found that AR expression was abnormal high and got correlation with Nanog. Then, by labeling cellular endogenous Nanog with green fluorescent protein (GFP) through CRISPR/Cas9 system, it verified the co-localization of AR and Nanog in HCC cells. With in vitro experiments, we demonstrated the axis can promote HCC cells stemness, which effect is in a Nanog-dependent manner and through activating its transcription. And the xenografted tumor experiments confirmed the axis effect on tumorigenesis facilitation in vivo. Above all, we revealed a new sight of androgen/AR axis roles in HCC and provided a potential way for suppressing the axis in HCC therapy.

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“…The other major phenotypic output of common LBD mutations is antagonist-agonist switching (Supplementary Table 1), which likely explains the withdrawal syndrome observed after cessation of firstgeneration antagonists seen in 15-30% of patients (Small et al 2004). T878A confers agonist properties to flutamide and nilutamide, H875Y to nilutamide and W742C/L to bicalutamide (Veldscholte et al 1990, Suzuki et al 1996, Tan et al 1997, Hara et al 2003, Azad et al 2015, O'Neill et al 2015, Lallous et al 2016. Interestingly, O'Neill and coworkers recently demonstrated that T878A inhibited bicalutamide-activated W742L (O'Neill et al 2015) in what may represent the first evidence of antagonism arising from the heterodimerization of distinct AR mutants.…”

Section: Gata2 Oct1mentioning

confidence: 99%

“…T878A confers agonist properties to flutamide and nilutamide, H875Y to nilutamide and W742C/L to bicalutamide (Veldscholte et al 1990, Suzuki et al 1996, Tan et al 1997, Hara et al 2003, Azad et al 2015, O'Neill et al 2015, Lallous et al 2016. Interestingly, O'Neill and coworkers recently demonstrated that T878A inhibited bicalutamide-activated W742L (O'Neill et al 2015) in what may represent the first evidence of antagonism arising from the heterodimerization of distinct AR mutants. Another mutation that can confer antagonist-agonist switching is F877L, which was found to be activated by enzalutamide in cell lines (Balbas et al 2013, Joseph et al 2013, Korpal et al 2013.…”

Section: Gata2 Oct1mentioning

confidence: 99%

Androgen receptor signaling in castration-resistant prostate cancer: a lesson in persistence

Coutinho¹,

Day²,

Tilley³

et al. 2016

Endocrine-Related Cancer

151

122

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The androgen receptor (AR) signaling axis drives all stages of prostate cancer, including the lethal, drug-resistant form of the disease termed castration-resistant prostate cancer (CRPC), which arises after failure of androgen deprivation therapy (ADT). Persistent AR activity in spite of ADT and the second-generation AR-targeting agents enzalutamide and abiraterone is achieved in many cases by direct alterations to the AR signaling axis. Herein, we provide a detailed description of how such alterations contribute to the development and progression of CRPC. Aspects of this broad and ever-evolving field specifically addressed in this review include: the etiology and significance of increased AR expression; the frequency and role of gain-of-function mutations in the AR gene; the function of constitutively active, truncated forms of the AR termed AR variants and the clinical relevance of alterations to the activity and expression of AR coregulators. Additionally, we examine the novel therapeutic strategies to inhibit these classes of therapy resistance mechanisms, with an emphasis on emerging agents that act in a manner distinct from the current ligand-centric approaches. Throughout, we discuss how the central role of AR in prostate cancer and the constant evolution of the AR signaling axis during disease progression represent archetypes of two key concepts in oncology, oncogene addiction and therapy-mediated selection pressure.

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Development and exploitation of a novel mutant androgen receptor modelling strategy to identify new targets for advanced prostate cancer therapy

Cited by 27 publications

References 40 publications

Darolutamide is a potent androgen receptor antagonist with strong efficacy in prostate cancer models

Darolutamide is a potent androgen receptor antagonist with strong efficacy in prostate cancer models

Androgen/androgen receptor axis maintains and promotes cancer cell stemness through direct activation of Nanog transcription in hepatocellular carcinoma

Androgen receptor signaling in castration-resistant prostate cancer: a lesson in persistence

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