Abstract
The androgen receptor (AR) signalling pathway is the key driver in most prostate cancers (PCa), and is underpinned by several kinases both upstream and downstream of the AR. Many popular therapies for PCa that target the AR directly, however, have been circumvented by AR mutation, such as androgen receptor variants. Some upstream kinases promote AR signalling, including those which phosphorylate the AR and others that are AR-regulated, and androgen regulated kinase that can also form feed-forward activation circuits to promotes AR function. All of these kinases represent potentially druggable targets for PCa. There has generally been a divide in reviews reporting on pathways upstream of the AR and those reporting on AR-regulated genes despite the overlap that constitutes the promotion of AR signalling and PCa progression. In this review, we aim to elucidate which kinases—both upstream and AR-regulated—may be therapeutic targets and require future investigation and ongoing trials in developing kinase inhibitors for PCa.
Highlights
The biological effects of male sex hormones, androgens, on the target tissues are manifested by the androgen receptor (AR) to achieve a wide range of developmental as well as physiological responses
Given that the NTD is intrinsically disordered, anecdotal compound screening techniques will have to be used to find potential inhibitors rather than designed antagonists based on the structure [9], targeting of kinases that modulate the NTD may prove more successful in tumours that are driven by such AR variants (AR-V)
AR signalling increases EGFR and IGF1R transcription [142,143], and in normal prostate epithelium EGFR is degraded by prolonged AR signalling [64], this can be overcome by various mechanisms including increased autocrine and paracrine epidermal growth factor (EGF) expression [144,145] and potentially changes in associated tyrosine kinase 1 (ACK1) UBD interaction [71]
Summary
The biological effects of male sex hormones, androgens, on the target tissues are manifested by the androgen receptor (AR) to achieve a wide range of developmental as well as physiological responses. Androgens play a crucial role in the differentiation and maturation of the male reproductive organs and androgens are the major regulators of cell proliferation and cell death of the epithelial cells within the prostate gland [1,2]. It is, not surprising that the majority of prostate cancers (PCas) remain reliant on the AR signalling axis throughout their life [3–5]. There have been strives in developing new small molecules which can bind different AR domains reviewed in [9], the identification of other fundamental proteins in the AR signalling cascade to therapeutically target to reduce ADT resistance and treat CRPC is an active and ongoing area of research.
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