Novel therapeutic targets and proposed mechanisms of androgen resistance (text in red) in hormone refractory prostate cancer. (1) Hypersensitive Pathway: AR amplification, increased AR expression or alterations in corepressor/coactivator function. (2) Versatile receptor: mutations in the ligand-binding domain of the AR permitting nonandrogenic ligand binding. (3) Alternative routes: utilisation of AR machinery by alternative pathways, that is, PI3K/Akt. (4) Bypass pathways: bypassing of the AR and its cellular machinery entirely, that is, upregulation of the antiapoptotic protein Bcl-2. Therapeutic targets include: the adrenal steroid synthesis pathway, AR signalling, growth factor receptors (GFR), PTEN (phosphatase and tensin homolog) and PI3K (phosphatidylinositide 3-OH kinase) signalling, angiogenesis and apoptosis. HSP90 denotes heat shock protein 90; PIP2 phosphatidylinositol-4,5- bisphosphate; PIP3 phosphatidylinositol-3,4,5- triphosphate; Akt protein kinase B; mTOR mammalian target of rapamycin; oncogenes Ras, Raf, Mek, Erk; Bcl-2 antiapoptotic protein; APAF1 apoptotic peptidase activating factor 1; IAP inhibitor of apoptosis family (of which survivin is a member). Solid lines indicate promotion. Broken lines indicate inhibition.

Treatment flow chart for patients diagnosed with CRPC.