Unravelling the Role of Kinases That Underpin Androgen Signalling in Prostate Cancer

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.

Keywords: androgen receptor; androgen-regulated genes; kinase; prostate cancer.

Figure 1

A schematic summarising the phosphorylated sites within the androgen receptor which moderate its activity. The androgen receptor contains several serine (S), threonine (T), and tyrosine (Y) residues that can be phosphorylated to moderate localisation, stability, and transactivation activity. Amino terminus transactivation domain (NTD), the DNA binding domain (DBD), the Hinge region (HR), and the ligand-binding domain (LBD). The activation function 1 (AF1) region (yellow line) consist of the majority of Tau1 and Tau5 (dark blue lines). The activation function 2 (AF2) region (purple lines) in the LBD is primarily located in the 12th helix; however, parts of the 3rd and 4th helixes also make up the AF2 surface [33].

Figure 2

Key cellular pathways involving upstream and downstream kinases of the androgen receptor. Different functional groups are contained within different coloured ovoids. Within Cell Metabolism and the MAPK Pathway are subgroups represented by further coloured ovals. There are 24 AR-regulated kinases that are discussed in the main text, with other key kinases and molecules these kinases interact with included.