The Effect of F877L and T878A Mutations on Androgen Receptor Response to Enzalutamide

Prekovic, Stefan; Royen, Martin E. van; Voet, Arnout; Geverts, Bart; Houtman, René; Melchers, Diana; Zhang, Kam Y. J.; Broeck, Thomas Van den; Smeets, Elien; Spans, Lien; Houtsmuller, Adriaan B.; Joniau, Steven; Claessens, Frank; Helsen, Christine

doi:10.1158/1535-7163.mct-15-0892

Cited by 80 publications

(68 citation statements)

References 48 publications

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“…Additional studies to further dissect the differential recruitment of NCoR1 and its impact on androgen signaling will help to better understand the significance of this mutation for prostate cancer progression. An altered recruitment of coregulators has previously been reported for AR H875Y treated with DHT and the AR F877L/T878A double mutant bound by enzalutamide . Interestingly, altered transcriptomes and cofactor recruitment profiles have also been documented for clinically relevant estrogen receptor mutants …”

Section: Discussionmentioning

confidence: 69%

“…1b) while giving special care to the preserved interaction of the cyano group of the CF 3 -/Clsubstituted benzonitrile moiety to R753, which was identified as key interaction in other structural and modeling studies. 36 Inspection of the proposed binding mode of darolutamide to the antagonistic AR wild type conformer suggested a face-toface stacking interaction of the eastern pyrazole moiety to the indole group of W742 (Fig. 1c).…”

Section: Structural Interpretation Of the Darolutamide Antagonistic Pmentioning

confidence: 99%

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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: 69%

Section: Structural Interpretation Of the Darolutamide Antagonistic Pmentioning

confidence: 99%

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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“…Mutations in the ligand-binding domain that alter ligand specificity and sensitivity frequently increase after androgen ablation. The AR F877L mutation has been found in enzalutamide resistant patients and might allow for enzalutamide acting as an AR antagonist, especially when this mutation co-occurs with the T878A mutation in prostate cancer cells (31–33). Prolonged enzalutamide or apalutamide treatment might reposition the drug to eliminate steric clashes that promoted helix 12 terminus (H12) dislocation in AR (34).…”

Section: Discussionmentioning

confidence: 99%

Niclosamide and Bicalutamide Combination Treatment Overcomes Enzalutamide- and Bicalutamide-Resistant Prostate Cancer

Liu

Armstrong

Lou

et al. 2017

Molecular Cancer Therapeutics

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Activation of the androgen receptor (AR) and its splice variants is linked to advanced prostate cancer and drives resistance to antiandrogens. The roles of AR and AR variants in the development of resistance to androgen deprivation therapy (ADT) and bicalutamide treatment, however, are still incompletely understood. To determine whether AR variants play a role in bicalutamide resistance, we developed bicalutamide resistant LNCaP cells (LNCaP-BicR) and found that these resistant cells express significantly increased levels of AR variants, particularly AR-V7, both at the mRNA and protein levels. Exogenous expression of AR-V7 in bicalutamide sensitive LNCaP cells confers resistance to bicalutamide treatment. Knockdown of AR-V7 in bicalutamide and enzalutamide resistant CWR22Rv1, enzalutamide resistant C4-2B (C4-2B MDVR) and LNCaP-BicR cells reversed bicalutamide resistance. Niclosamide, a potent inhibitor of AR variants, significantly enhanced bicalutamide treatment. Niclosamide and bicalutamide combination treatment not only suppressed AR and AR variants expression and inhibited their recruitment to the PSA promoter, but also significantly induced apoptosis in bicalutamide and enzalutamide resistant CWR22Rv1 and C4-2B MDVR cells. In addition, combination of niclosamide with bicalutamide inhibited the growth of enzalutamide resistant tumors. In summary, our results demonstrate that AR variants, particularly AR-V7, drive bicalutamide resistance and that targeting AR-V7 with niclosamide can re-sensitize bicalutamide resistant cells to bicalutamide treatment. Furthermore, combination of niclosamide with bicalutamide inhibits enzalutamide resistant tumor growth, suggesting that the combination of niclosamide and bicalutamide could be a potential cost effective strategy to treat advanced prostate cancer in patients, including those who fail to respond to enzalutamide therapy.

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“…The current more intensive androgen deprivation treatments in CRPC, including abiraterone or enzalutamide, may thereby further select for gain-of-function AR mutations to allow the restoration of AR signaling in tumor cells. Recent studies on PCa cell lines and patient samples have revealed multiple AR point mutations, including treatment-induced F877L and T878A [8, 10, 29, 30]. The majority of these mutations occur within the LBD domain and function to alter the ligand binding specificity of AR.…”

Section: Discussionmentioning

confidence: 99%

A novel nonsense mutation in androgen receptor confers resistance to CYP17 inhibitor treatment in prostate cancer

et al. 2016

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The standard treatment for prostate cancer (PCa) is androgen deprivation therapy (ADT) that blocks transcriptional activity of androgen receptor (AR). However, ADT invariably leads to the development of castration-resistant PCa (CRPC) with restored activity of AR. CRPC can be further treated with CYP17 inhibitors to block androgen synthesis pathways, but most patients still relapse after a year of such treatment. The mechanisms that drive this progression are not fully understood, but AR activity, at least in a subset of cancers, appears to be restored again. Importantly, AR mutations are more frequently detected in this type of cancer. By analyzing tumor biopsy mRNA from CRPC patients who had developed resistance to CYP17 inhibitor treatment, we have identified a novel nonsense mutation (Q784*) at the ligand binding domain (LBD) of AR, which produces a C-terminal truncated AR protein that lacks intact LBD. This AR-Q784* mutant is transcriptionally inactive, but it is constitutively expressed in the nucleus and can bind to DNA in the absence of androgen. Significantly, our results show that AR-Q784* can heterodimerize with, and enhance the transcriptional activity of, full-length AR. Moreover, expressing AR-Q784* in an AR positive PCa cell line enhances the chromatin binding of endogenous AR and the recruitment of p300 coactivator under the low androgen condition, leading to increased cell growth. This activity of AR-Q784* mimics the function of some AR splice variants, indicating that CYP17 inhibitor treatment in CRPC may select for LBD-truncated forms of AR to restore AR signaling.

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The Effect of F877L and T878A Mutations on Androgen Receptor Response to Enzalutamide

Cited by 80 publications

References 48 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

Niclosamide and Bicalutamide Combination Treatment Overcomes Enzalutamide- and Bicalutamide-Resistant Prostate Cancer

A novel nonsense mutation in androgen receptor confers resistance to CYP17 inhibitor treatment in prostate cancer

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