Dataset Information

Inhibition of the Wnt/?-Catenin Pathway Overcomes Resistance to Enzalutamide in Castration-Resistant Prostate Cancer.

ABSTRACT: Enzalutamide is a second-generation nonsteroidal antiandrogen clinically approved for the treatment of castration-resistant prostate cancer (CRPC), yet resistance to endocrine therapy has limited its success in this setting. Although the androgen receptor (AR) has been associated with therapy failure, the mechanisms underlying this failure have not been elucidated. Bioinformatics analysis predicted that activation of the Wnt/?-catenin pathway and its interaction with AR play a major role in acquisition of enzalutamide resistance. To validate the finding, we show upregulation of ?-catenin and AR in enzalutamide-resistant cells, partially due to reduction of ?-TrCP-mediated ubiquitination. Although activation of the Wnt/?-catenin pathway in enzalutamide-sensitive cells led to drug resistance, combination of ?-catenin inhibitor ICG001 with enzalutamide inhibited expression of stem-like markers, cell proliferation, and tumor growth synergistically in various models. Analysis of clinical datasets revealed a molecule pattern shift in different stages of prostate cancer, where we detected a significant correlation between AR and ?-catenin expression. These data identify activation of the Wnt/?-catenin pathway as a major mechanism contributing to enzalutamide resistance and demonstrate the potential to stratify patients with high risk of said resistance.Significance: Wnt/?-catenin inhibition resensitizes prostate cancer cells to enzalutamide. Cancer Res; 78(12); 3147-62. ©2018 AACR.

SUBMITTER: Zhang Z

PROVIDER: S-EPMC6004251 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Inhibition of the Wnt/β-Catenin Pathway Overcomes Resistance to Enzalutamide in Castration-Resistant Prostate Cancer.

Zhang Zhuangzhuang Z Cheng Lijun L Li Jie J Farah Elia E Atallah Nadia M NM Pascuzzi Pete E PE Gupta Sanjay S Liu Xiaoqi X

Cancer research 20180426 12

Enzalutamide is a second-generation nonsteroidal antiandrogen clinically approved for the treatment of castration-resistant prostate cancer (CRPC), yet resistance to endocrine therapy has limited its success in this setting. Although the androgen receptor (AR) has been associated with therapy failure, the mechanisms underlying this failure have not been elucidated. Bioinformatics analysis predicted that activation of the Wnt/β-catenin pathway and its interaction with AR play a major role in acqu ...[more]

PMID: 29700003

Similar Datasets

Project description:BackgroundWnt signaling is a cellular pathway involved in embryogenesis, development, and neoplasia. Wnt-pathway activation may accelerate prostate cancer androgen-independent growth and mediate antiandrogen resistance. Since 10-20% of advanced prostate cancers harbor Wnt-activating mutations, we aimed to characterize the clinical features and response to novel antiandrogens in such patients.ObjectiveTo determine whether men with metastatic castration-resistant prostate cancer (mCRPC) who harbor Wnt-pathway mutations have poorer responses to first-line novel hormonal therapies: abiraterone/enzalutamide.Design, setting, and participantsPatients with mCRPC who received first-line abiraterone or enzalutamide were retrospectively evaluated. Using tumor DNA analyses, we queried for activating mutations in CTNNB1 or inactivating mutations in APC or RNF43, all of which are predicted to stimulate Wnt signaling. Presence or absence of at least one Wnt-activating alteration was correlated with clinical-pathologic characteristics and treatment outcomes.Outcome measurements and statistical analysisTime to prostate-specific antigen (PSA) progression, overall survival (OS), and PSA response were measured. Cox regression models were used to test associations between Wnt status and clinical-pathologic outcomes; Kaplan-Meier and log-rank analyses were used to compare time-to-event endpoints.Results and limitationsOf 137 patients evaluated, 11% (n=15) had tumor DNA analysis showing at least one Wnt-stimulating alteration. Patients with Wnt-activating mutations had numerically fewer T3/T4 tumors than Wnt wild-type patients (31% vs 51%), but were otherwise generally balanced. Median time to PSA progression on first-line abiraterone/enzalutamide was shorter in Wnt-activated patients (6.5 vs 9.6mo, hazard ratio [HR] 2.34, p=0.003), as was OS (23.6 vs 27.7mo, HR 2.28, p=0.01). PSA responses were numerically worse in Wnt-activated patients (53% vs 75%, p=0.12). Presence of Wnt-activating alterations (adjusted HR [aHR] 2.33, p=0.007) and use of previous chemotherapy (aHR 1.83, p=0.004) were both independently associated with increased hazard of progression.ConclusionsPatients with somatic Wnt-pathway activating mutations have worse outcomes to first-line abiraterone/enzalutamide than Wnt wild-type patients. Our data suggest that additional genomically informed therapies are needed for this relevant subset of mCRPC patients.Patient summaryIn this report, we retrospectively examined outcomes of metastatic prostate cancer patients with or without Wnt-pathway mutations who received abiraterone or enzalutamide for the first time, in order to examine whether these mutations affect the prognosis. Our study suggested that patients who have Wnt-pathway activating mutations derived less benefit from abiraterone and enzalutamide when compared to patients without these mutations. We conclude that Wnt-pathway mutations might decrease the effectiveness of abiraterone and enzalutamide, and we propose that the Wnt pathway might be a good therapeutic target for these patients, in order to potentially reverse or prolong resistance to abiraterone and enzalutamide in men with Wnt mutations.

Dataset Information

Inhibition of the Wnt/?-Catenin Pathway Overcomes Resistance to Enzalutamide in Castration-Resistant Prostate Cancer.

Publications

Inhibition of the Wnt/β-Catenin Pathway Overcomes Resistance to Enzalutamide in Castration-Resistant Prostate Cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets