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Enzalutamide-resistant castration-resistant prostate cancer: challenges and solutions

Authors Tucci M, Zichi C, Buttigliero C, Vignani F, Scagliotti GV, Di Maio M

Received 9 May 2018

Accepted for publication 21 September 2018

Published 24 October 2018 Volume 2018:11 Pages 7353—7368


Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Cristina Weinberg

Peer reviewer comments 2

Editor who approved publication: Dr Faris Farassati

Marcello Tucci,1,* Clizia Zichi,1,* Consuelo Buttigliero,1 Francesca Vignani,2 Giorgio V Scagliotti,1 Massimo Di Maio2

1Division of Medical Oncology, Department of Oncology, University of Turin, San Luigi Gonzaga Hospital, 10043 Orbassano, Turin, Italy; 2Division of Medical Oncology, Ordine Mauriziano Hospital, Torino, Italy

*These authors contributed equally to this work

Abstract: The new-generation hormonal agent enzalutamide has been approved for the treatment of metastatic castration-resistant prostate cancer (CRPC), in both post- and predocetaxel setting, due to the significant improvement in overall survival. More recently, enzalutamide also showed impressive results in the treatment of men with nonmetastatic CRPC. Unfortunately, not all patients with CRPC are responsive to enzalutamide, and even in responders, benefits are limited by the development of drug resistance. Adaptive resistance of metastatic prostate cancer to enzalutamide treatment can be due to the activation of both androgen receptor (AR)-dependent pathways (expression of constitutively active AR splice variants, AR point mutations, gene amplification and overexpression) and mechanisms independent of AR signaling pathway (altered steroidogenesis, upregulation of the glucocorticoid receptor, epithelial–mesenchymal transition, neuroendocrine transformation, autophagy and activation of the immune system). In this review, we focus on resistance mechanisms to enzalutamide, exploring how we could overcome them through novel therapeutic options.

Keywords: prostate cancer, enzalutamide, hormonal treatment, mechanisms of resistance, castration-resistant prostate cancer, androgen receptor

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