Emerging mechanisms of enzalutamide resistance in prostate cancer

  title={Emerging mechanisms of enzalutamide resistance in prostate cancer},
  author={Frank Claessens and Christine Helsen and Stefan Prekovic and Thomas Van den Broeck and Lien Spans and Hendrik van Poppel and Steven Joniau},
  journal={Nature Reviews Urology},
The majority of prostate cancers are hormone-dependent at diagnosis highlighting the central role of androgen signalling in this disease. Surprisingly, most forms of castration-resistant prostate cancer (CRPC) are still dependent on the androgen receptor (AR) for survival. Therefore, the advent of new AR-targeting drugs, such as enzalutamide, is certainly beneficial for the many patients with metastatic CRPC. Indeed, this compound provides a substantial survival benefit—but it is not curative… 

The evolving role of enzalutamide on the treatment of prostate cancer.

The milestones in the development of enzalutamide in patients with prostate cancer are summarized and special focus is placed on the results of the STRIVE Phase II clinical trial comparing head to head enzalUTamide and bicalutamide on patients with nonmetastatic and mCRPC who have failed androgen deprivation.

Metastatic castration-resistant prostate cancer: targeting the mechanisms of resistance to abiraterone acetate and enzalutamide

The aim of this review is to summarize the main data available on the evaluation of the multiple levels of development of resistance to next-generation AR-directed therapies.

Androgen–glucocorticoid interactions in the era of novel prostate cancer therapy

Understanding the biological role of glucocorticoid-related mechanisms that can cause iatrogenic stimulation of prostate cancer growth have emerged, which might contribute to drug resistance and disease progression despite optimal ADT.

Targeting molecular resistance in castration-resistant prostate cancer

Current knowledge of mechanisms of resistance to the currently approved treatments, development of adjunctive therapies, and identification of new pathways being targeted for therapeutic purposes are reviewed.

Enzalutamide in Metastatic Castration Resistant Prostate Cancer

Enzalutamide is approved for treatment of patients with mCRPC, either in docetaxel-naive or -resistant disease, and several resistance mechanisms involving the androgen-signaling pathway have been identified.

Mechanisms of resistance in castration-resistant prostate cancer (CRPC)

Multiple mechanisms of resistance to ADT and currently approved CRPC treatments will help guide future research into targeted therapies, and some of the mechanisms by which these agents fail are unique, many share similarities to the mechanisms contributing to CRPC progression.

Inhibition of Serum Response Factor Improves Response to Enzalutamide in Prostate Cancer

This study tested SRF inhibition in vitro and in vivo to assess SRF as a potential target in Castrate-resistant prostate cancer and supports the use of SRF inhibitors to improve response to enzalutamide.

Cross-Resistance to Abiraterone and Enzalutamide in Castration Resistance Prostate Cancer Cellular Models Is Mediated by AR Transcriptional Reactivation

Androgen deprivation therapy (ADT) and novel hormonal agents (NHAs) (Abiraterone and Enzalutamide) are the goal standard for metastatic prostate cancer (PCa) treatment and a subsequent castration resistance status (CRPC) is commonly developed.

Androgen receptor antagonists produced by Streptomyces overcome resistance to enzalutamide

There is an urgent need to develop new AR antagonists with new structures that show potent AR antagonist activity in prostate cancer cells and could overcome resistance to enzalutamide.

Extracellular Vesicle-Mediated Reversal of Paclitaxel Resistance in Prostate Cancer.

It is suggested that EVs represent a potentially novel therapeutic treatment option for castrate resistant prostate cancer and the reversal of taxane resistance and tumorigenic phenotype in PCa cells after EVs treatment.



ARN-509: a novel antiandrogen for prostate cancer treatment.

ARS-509 exhibits characteristics predicting a higher therapeutic index with a greater potential to reach maximally efficacious doses in man than current AR antagonists, and offers preclinical proof of principle for ARN-509 as a promising therapeutic in bothCastration-sensitive and castration-resistant forms of prostate cancer.

Biologic and clinical significance of androgen receptor variants in castration resistant prostate cancer.

This review focuses on the etiology, characterization, biological properties, and emerging data contributing to the clinical characteristics of AR variants, and suggests approaches to full-length AR and AR variant biomarker validation, assessment, and systemic targeting in the clinic.

Adaptation or selection—mechanisms of castration-resistant prostate cancer

Current research is focused on not only understanding the cellular mechanisms of CRPC, but also defining critical pathways that can be targeted with combinatorial therapies in castration-resistant cancer cells.

Androgen receptor splice variants mediate enzalutamide resistance in castration-resistant prostate cancer cell lines.

This study shows that cells with AR gene rearrangements expressing both full-length and AR-Vs are androgen independent and enzalutamide resistant, but selective knock-down of AR-V expression inhibited androgen-independent growth and restored responsiveness to androgens and antiandrogens.

AR variant ARv567es induces carcinogenesis in a novel transgenic mouse model of prostate cancer.

Findings indicate that ARv567es could induce tumorigenesis de novo and signifies the critical role of AR-Vs in CRPC, and the Pb-ARv 567es mouse could provide a novel model in which the roles of AR variants in prostate cancer progression can be examined.

Increased survival with enzalutamide in prostate cancer after chemotherapy.

Enzalutamide significantly prolonged the survival of men with metastatic castration-resistant prostate cancer after chemotherapy, and was shown with respect to all secondary end points.

Implementing newer agents for the management of castrate‐resistant prostate cancer: what is known and what is needed?

Suggestions are provided on the continued relevance of conventional approaches to first‐ and second‐line treatment in mCRPC, the potential role of novel treatments, and factors that may influence the choice of hormonal agents and/or chemotherapy.