Small Molecule Therapeutics Targeting Ligand-Independent Activation of Androgen Receptor in Prostate Cancer

Prostate cancer (PCa) is the second most diagnosed malignancy in males globally. The steroid receptor transcription factor called androgen receptor (AR) plays a pivotal role in the functioning of the prostate gland. Dysregulation of the AR signalling pathway is associated with development of PCa and its progression to castration-resistant prostate cancer (CRPC), which happens inevitably after androgen deprivation therapy (ADT). Reactivation of AR signalling after ADT by mechanisms like AR mutations/overexpression/amplification, differential splicing of AR transcripts, intra-tumoural androgen synthesis, alteration of AR co-regulators, and ligand-independent activation of AR, leads to the development of CRPC. Ligand-independent activation (transactivation) of AR is mediated by crosstalk between kinases (PI3K/Akt, MAPK), growth factors (EGF, IGF-1), and cytokines (IL-6). Despite continuous research in the development of targeted therapeutics against AR, the prognosis remains unfavourable in PCa as reflected by adverse outcomes like bone metastasis and CRPC associated with high rate of patient mortality. Therapeutic targeting of AR transactivation pathways by small molecules can provide a promising treatment option for CRPC patients. In this review, the ligand-independent activation of AR and the potential small molecules, which target the key components of associated pathways and are currently evaluated in clinical trials, have been summarised.