Enzalutamide: targeting the androgen signalling pathway in metastatic castration‐resistant prostate cancer

Abstract

Significant progress has been made in the understanding of the underlying cancer biology of castration‐resistant prostate cancer (CRPC) with the androgen receptor (AR) signalling pathway remaining implicated throughout the prostate cancer disease continuum. Reactivation of the AR signalling pathway is considered to be a key driver of CRPC progression and, as such, the AR is a logical target for therapy in CRPC. The objective of this review was to understand the importance of AR signalling in the treatment of patients with metastatic CRPC (mCRPC) and to discuss the clinical benefits associated with inhibition of the AR signalling pathway. A search was conducted to identify articles relating to the role of AR signalling in CRPC and therapies that inhibit the AR signalling pathway. Current understanding of prostate cancer has identified the AR signalling pathway as a logical target for the treatment of CRPC. Available therapies that inhibit the AR signalling pathway include AR blockers, androgen biosynthesis inhibitors, and AR signalling inhibitors. Enzalutamide, the first approved AR signalling inhibitor, has a novel mode of action targeting AR signalling at three key stages. The direct mode of action of enzalutamide has been shown to translate into clinical responses in patients with mCRPC. In conclusion, the targeting of the AR signalling pathway in patients with mCRPC results in numerous clinical benefits. As the number of treatment options increase, more trials evaluating the sequencing and combination of treatments are required. This review highlights the continued importance of targeting a key driver in the progression of CRPC, AR signalling, and the clinical benefits associated with inhibition of the AR signalling pathway in the treatment of patients with CRPC.

KLF4 functions as an activator of the androgen receptor through reciprocal feedback

“…We analyzed the relationship between KLF4 and AR signaling and observed that AR-expressing cells LNCaP, LNCaP-AR and 22Rv1 had higher KLF4 expression than did cells without AR expression PC3, DU145 and RasB1 (Figure 1a). In LNCaP and LNCaP-AR cells, KLF4 messenger RNA (mRNA) and protein levels increased after dihydrotestosterone (DHT) treatment (Figures 1b and c), but decreased after treatment with MDV3100, an AR antagonist 22, 23 (Figures 1d and e), suggesting an association between KLF4 and AR signaling in the same cell signaling pathway in AR-positive prostate cancer cells. Moreover, KLF4 mRNA levels increased in LNCaP cells transfected with an AR expression vector (Figure 1f).…”

Androgen deprivation therapy for androgen receptor‐positive advanced salivary duct carcinoma: A nationwide case series of 35 patients in The Netherlands

“…The OS of ADT‐treated patients was significantly better than of best supportive care patients. However, as not all patients responded to ADT, future research should focus on biomarkers that predict the response of patients to ADT and mechanisms of intrinsic and acquired resistance to ADT . One may assume that female patients could have less benefit from ADT due to the lower physiological presence of androgen, and, thus, less stimulation of androgen receptor‐positive tumor cells.…”

The hallmarks of castration-resistant prostate cancers

“…Among latest therapeutic strategies developed and FDA-approved, Enzalutamide is a novel antiandrogen selected for novel clinical development with promising results [22], presenting great affinity for the AR, lacks agonists effects and inhibits not only ligand binding to the receptor in a competitive manner but also AR nuclear translocation and DNA fixation. Clinical results showed a slowing down in cancer cell growth, induction of cancer cell apoptosis and tumor regression [23].…”