Androgen Receptor Signaling in the Development of Castration-Resistant Prostate Cancer

Abstract

Most prostate cancers are androgen-sensitive malignancies whose growths depend on the transcriptional activity of the androgen receptor (AR). In the 1940s, Charles Huggins demonstrated that the surgical removal of testes in men can result in a dramatic improvement in symptoms and can induce prostate cancer regression. Since then, androgen deprivation therapies have been the standard first-line treatment for advanced prostate cancer, including: surgical castration, medical castration, antiandrogens, and androgen biosynthesis inhibitors. These therapies relieve symptoms, reduce tumor burden, and prolong patient survival, while having relatively modest side effects. Unfortunately, hormone deprivation therapy rarely cures the cancer itself. Prostate cancer almost always recurs, resulting in deadly castration-resistant prostate cancer. The underlying escape mechanisms include androgen receptor gene/enhancer amplification, androgen receptor mutations, androgen receptor variants, coactivator overexpression, intratumoral de novo androgen synthesis, etc. Whereas, the majority of the castration-resistant prostate cancers continuously rely on the androgen axis, a subset of recurrent cancers have completely lost androgen receptor expression, undergone divergent clonal evolution or de-differentiation, and become truly androgen receptor-independent small-cell prostate cancers. There is an urgent need for the development of novel targeted and immune therapies for this subtype of prostate cancer, when more deadly small-cell prostate cancers are induced by thorough androgen deprivation and androgen receptor ablation.

Keywords: androgen deprivation therapy (ADT); androgen receptor (AR); antiandrogen; castration-resistant prostate cancer (CRPC); prostate cancer (PCa); small-cell prostate cancer (SCPC).

Figure 1

The unique molecular features of the androgen receptor and its coregulator recruitment. (A) The primary sequence of the androgen receptor contains several functional domains: NH₂-terminal Activation Function 1 (AF1), the central DBD, the carboxyl-terminal LBD, and two AR-specific FxxLF and WxxLF motifs. (B) Schematic diagram of homodimeric androgen receptor bound to a palindromic androgen response element (ARE). Dimerization of the androgen receptor is mediated by both DBD and LBD. Shown in the diagram are FxxLF motif-mediated N/C interaction, recruitment of the SRC/p160 by AF1 and AF2, recruitment of FxxLF motif-containing ARA proteins by AF2, and recruitment of MAGE-A11 through the AR NH₂-terminal extended FxxLF motif. Competition likely exists among different FxxLF, WxxLF, and LxxLF motifs for binding to the same AF2 site on AR LBD (1). SRC, steroid receptor coactivator; ARA, AR-associated protein; AF1, activation function 1; AF2, activation function 2, a hydrophobic cleft in the LBD; ARE, androgen response element; DBD, DNA binding domain; LBD, ligand binding domain.

Figure 2

Chemical structures of androgens and antiandrogens. (A) Two main androgens, testosterone (T), and dihydrotestosterone (DHT). (B) First-generation antiandrogens, cyproterone acetate (Androcur), Flutamide (Eulexin), Bicalutamide (Casodex), Nilutamide (Nilandron). 2-hydroxyflutamide is the major active metabolite of flutamide in the body. (C) Representative second-generation antiandrogens, Enzalutamide (Xtandi), Apalutamide (Erleada), and Darolutamide (Nubeqa). Structures are adopted from Wikipedia.

Figure 3

Evolution of prostate cancer under androgen deprivation therapy. Androgen sensitive primary prostate cancers arise from prostate luminal epithelial cells, which have undergone genetic alterations, such as mutation of PTEN tumor suppressor (107) or chromosomal rearrangement resulting in the TMPRSS2/ERG chimeric gene (108). Upon androgen deprivation including castration and the first-generation antiandrogen treatment, most HNPC will develop into CRPC, whose survival and growth still depends on androgen receptor signaling. After treatment with more potent androgen deprivation therapies such as second-generation antiandrogens, the majority of CRPC manages to develop novel mechanisms to maintain active androgen signaling axis to confer resistance, whereas a subset of CRPC will irreversibly lose androgen receptor expression, undergo divergent clonal evolution or de-differentiation, and become truly androgen-independent small-cell prostate cancer. ADT, androgen deprivation therapy; HNPC, hormone-naïve prostate cancer; CRPC, castration-resistant prostate cancer; SCPC, small-cell prostate cancer.