Castration resistance is in part attributable to aberrant activation of androgen receptor (AR) signaling by the intracrine activation of androgen precursors derived from adrenal glands. To overcome this, novel AR pathway inhibitors (ARPIs) that suppress androgen synthesis by CYP17 inhibition or AR activation by antiandrogen effects have been developed. However, primary or acquired resistance to these ARPIs occurs; in turn attributable, at least in part, to the maintained androgen milieu despite intensive suppression of AR signaling similar to castration resistance. In addition to the classical pathway to produce potent androgens such as testosterone and dihydrotestosterone, the alternative pathway and the backdoor pathway which bypasses testosterone to produce dihydrotestosterone have been shown to play a role in intratumor steroidogenesis. Furthermore, the 11β-hydroxyandrostenedione pathway to produce the potent oxygenated androgens 11-ketotestosterone and 11-ketodihydrotestosterone has been suggested to be functional in prostate cancer. These steroidogenesis pathways produce potent androgens that promote tumor resistance to endocrine therapy including novel ARPIs. Here, we overview the current evidence on the pathological androgen milieu by altered metabolism and transport in prostate cancer, leading to resistance to endocrine therapy.
Keywords: Androgen; CRPC; Metabolism; Steroidogenesis; Transport.
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