Enzalutamide: looking back at its preclinical discovery

Ha, Yun‐Sok; Kim, Isaac Yi

doi:10.1517/17460441.2014.918947

Cited by 10 publications

(8 citation statements)

References 47 publications

(50 reference statements)

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“…In treating men with CRPC, enzalutamide is a key second generation anti-androgen used widely due to its ease of administration as well as a low toxicity profile [6]. Notwithstanding, as with all second-generation androgen manipulations, resistance to enzalutamide treatment emerges inevitably with a median time of 4.8 months [32].…”

Section: Discussionmentioning

confidence: 99%

“…Enzalutamide is a FDA-approved second-generation androgen receptor (AR) antagonist that blocks ligand binding, nuclear translocation, DNA binding, and coactivator recruitment of ARs [6]. In multiple clinical trials, enzalutamide has been shown to prolong overall and progression-free survival, improve patient-reported quality of life, and delay the development of skeletal-related complications in men with metastatic CRPC who are chemotherapy naïve or have previously received docetaxel [7–9].…”

Section: Introductionmentioning

confidence: 99%

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TCF4 induces enzalutamide resistance via neuroendocrine differentiation in prostate cancer

et al. 2019

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In treating patients with castration resistant prostate cancer (CRPC), enzalutamide, the second-generation androgen receptor (AR) antagonist, is an accepted standard of care. However, clinical benefits are limited to a median time of 4.8 months because resistance inevitably emerges. To determine the mechanism of treatment resistance, we carried out a RNA sequence analysis and found increased expression levels of neuroendocrine markers in the enzalutamide-resistant LNCaP human prostate cancer (CaP) cell line when compared to the parental cell line. Subsequent studies demonstrated that Transcription Factor-4 (TCF4), a transcription factor implicated in WNT signaling, mediated neuroendocrine differentiation (NED) in response to enzalutamide treatment and was elevated in the enzalutamide-resistant LNCaP. In addition, we observed that PTHrP mediated enzalutamide resistance in tissue culture and inducible TCF4 overexpression resulted in enzalutamide-resistance in a mouse xenograft model. Finally, small molecule inhibitors of TCF4 or PTHrP partially reversed enzalutamide resistance in CaP cells. When tissues obtained from men who died of metastatic CaP were examined, a positive correlation was found between the expression levels of TCF4 and PTHrP. Taken together, the current results indicate that TCF4 induces enzalutamide resistance via NED in CaP.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

TCF4 induces enzalutamide resistance via neuroendocrine differentiation in prostate cancer

et al. 2019

Self Cite

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show abstract

“…In treating men with CRPC, enzalutamide is a key second generation anti-androgen used widely due to its ease of administration as well as a low toxicity profile (6). Notwithstanding, as with all second-generation androgen manipulations, resistance to enzalutamide treatment emerges inevitably with a median time of 4.8 months (31).…”

Section: Discussionmentioning

confidence: 99%

TCF4 induces enzalutamide resistance via neuroendocrine differentiation in prostate cancer

Lee

Kim

Kwon

et al. 2019

Preprint

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26In treating patients with castration resistant prostate cancer (CRPC), enzalutamide, the second-27 generation androgen receptor (AR) antagonist, is an accepted standard of care. However, clinical 28 benefits are limited to a median time of 4.8 months because resistance inevitably emerges. To 29 determine the mechanism of treatment resistance, we carried out a RNA sequence analysis and 30 found increased expression levels of neuroendocrine markers in the enzalutamide-resistant LNCaP 31 human prostate cancer (CaP) cell line when compared to the parental cell line. Subsequent studies 32 demonstrated that TCF4, a transcription factor implicated in Wnt signaling, mediated 33 neuroendocrine differentiation (NED) in response to enzalutamide treatment and was elevated in 34 the enzalutamide-resistant LNCaP. In addition, we observed that PTHrP mediated enzalutamide 35 resistance in tissue culture and inducible TCF4 overexpression resulted in enzalutamide-resistance 36 in a mouse xenograft model. Finally, small molecule inhibitors of TCF4 or PTHrP partially 37 reversed enzalutamide resistance in CaP cells. When tissues obtained from men who died of 38 metastatic CaP were examined, a positive correlation was found between the expression levels of 39 TCF4 and PTHrP. Taken together, the current results indicate that TCF4 induces enzalutamide 40 resistance via NED in CaP. 42 Prostate cancer (CaP) is the most common non-cutaneous cancer diagnosed among men and the 43 second leading cause of male cancer deaths in the United States (1). In 2017, it is estimated that 44 26,730 men died from CaP. Although radiation and surgery are quite effective for localized disease, 45 approximately 30% eventually recur following a definitive therapy. More importantly, there is no 46 effective cure for men who present with metastatic CaP as the 5-year relative survival rate is only 47 29% (1). In patients with a metastatic disease, medical or surgical castration is generally the 48 accepted first-line therapy. Yet, castration-resistant prostate cancer (CRPC) eventually emerges 49 with a median time of 18-24 months (2, 3). Once CRPC develops, secondary hormonal 50 manipulation, immunotherapy, and chemotherapy are marginally effective and the average life 51 expectancy is ~5 years (4, 5). 52Enzalutamide is a FDA-approved second-generation androgen receptor (AR) antagonist 53 that blocks ligand binding, nuclear translocation, DNA binding, and coactivator recruitment of 54 ARs (6). In multiple clinical trials, enzalutamide has been shown to prolong overall and 55 progression-free survival, improve patient-reported quality of life, and delay the development of 56 skeletal-related complications in men with metastatic CRPC who are chemotherapy naïve or have 57 previously received docetaxel (7-9). However, despite the significant initial therapeutic benefits 58 of enzalutamide, resistance inevitably occurs with a median time of 4.8 months. Although the 59 precise mechanistic details underlying the emergence of enzalutamide resistance is largely 60 ...

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“…Unlike the first generation of AR antagonists, enzalutamide lacks AR agonistic activity (for review, see Ha & Kim 2014) and, furthermore, has been reported to bind to AR with approximately eight-fold higher affinity than bicalutamide (Tran et al 2009). …”

Section: Discussionmentioning

confidence: 99%

Preclinical evaluation of the AR inhibitor enzalutamide in triple-negative breast cancer cells

Caiazza¹,

Murray²,

Madden³

et al. 2016

Endocrine-Related Cancer

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The androgen receptor (AR) is present in approximately 80% of invasive breast cancer patients and in up to 30% of patients with triple-negative breast cancer (TNBC). Therefore, our aim was to investigate the targeting of AR as a possible hormonal approach to the treatment of TNBC. Analysis of 2091 patients revealed an association between AR expression and poor overall survival, selectively in patients with the basal subtype of breast cancer, the vast majority of which are TNBC. IC 50 values for the secondgeneration anti-androgen enzalutamide across 11 breast cancer cell lines varied from 4 µM to >50 µM. The activity of enzalutamide was similar in TN and non-TN cell lines but was dependent on the presence of AR. Enzalutamide reduced clonogenic potential and cell growth in a 3D matrix in AR-positive cells. In addition, enzalutamide also inhibited cell migration and invasion in an AR-dependent manner. Enzalutamide appeared to mediate these processes through down-regulation of the transcription factors AP-1 and SP-1. The first-generation anti-androgen flutamide similarly blocked cell growth, migration and invasion. AR-positive TNBC cells clustered separately from AR-negative cells based on an androgen-related gene expression signature, independently of TNBC subtype. We conclude that targeting of the AR with drugs such as enzalutamide may provide an alternative treatment strategy for patients with AR-positive TNBC.

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Enzalutamide: looking back at its preclinical discovery

Cited by 10 publications

References 47 publications

TCF4 induces enzalutamide resistance via neuroendocrine differentiation in prostate cancer

TCF4 induces enzalutamide resistance via neuroendocrine differentiation in prostate cancer

TCF4 induces enzalutamide resistance via neuroendocrine differentiation in prostate cancer

Preclinical evaluation of the AR inhibitor enzalutamide in triple-negative breast cancer cells

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