Androgen Receptor-Dependent and -Independent Mechanisms Involved in Prostate Cancer Therapy Resistance

Abstract

Despite the initial efficacy of androgen deprivation in prostate cancer, virtually all patients progress to castration-resistant prostate cancer (CRPC). Androgen receptor (AR) signaling is critically required for CRPC. A new generation of medications targeting AR, such as abiraterone and enzalutamide, has improved survival of metastatic CRPC (mCRPC) patients. However, a significant proportion of patients presents with primary resistance to these agents, and in the remainder, secondary resistance will invariably develop, which makes mCRPC the lethal form of the disease. Mechanisms underlying progression to mCRPC and treatment resistance are extremely complex. AR-dependent resistance mechanisms include AR amplification, AR point mutations, expression of constitutively active AR splice variants, and altered intratumoral androgen biosynthesis. AR-independent resistance mechanisms include glucocorticoid receptor activation, immune-mediated resistance, and neuroendocrine differentiation. The development of novel agents, such as seviteronel, apalutamide, and EPI-001/EPI-506, as well as the identification and validation of novel predictive biomarkers of resistance, may lead to improved therapeutics for mCRPC patients.

Keywords: abiraterone; androgen receptor; castration-resistant prostate cancer; enzalutamide; progression; resistance mechanisms.

Figure 1

The human androgen receptor gene and protein. This figure depicts the gene and protein structures for the AR-FL. The AR is located on the X chromosome (Xq11.2) and is comprised of eight exons. AR-FL contains the NTD (encoded by exon 1), the DBD (encoded by exons 2–3), the hinge region (encoded by exon 4) and the LBD (encoded by exons 5–8). The strong transcriptional activity in the NTD can be attributed to the AF-1, while the LBD contains the weaker AF-2. Two major transactivation units are present in the AF-1: TAU-1 and TAU-5. Abbreviations: AF-1, activation function 1; AF-2, activation function 2; AR-FL, androgen receptor full length; DBD, DNA-binding domain; LBD, ligand-binding domain; NTD, N-terminal transactivation domain; TAU-1, transactivation unit 1; TAU-5, transactivation unit 5; UTR, untranslated region.

Figure 2

AR signaling axis, and mechanisms of AR targeted inhibition. CYP17A1 is the enzyme responsible for the conversion of androgen precursors (i.e., pregnenolone and progesterone; represented by the light purple circles) to DHEA, while HSD3β1 converts DHEA to AD, AKR1C3 converts AD to testosterone (represented by the blue circles) and finally 5α-reductase converts testosterone to dihydrotestosterone (DHT; represented by the green circles). DHT-mediated activation of the AR causes a conformational change where the AR dimerizes, which then triggers AR translocation into the nucleus. Abiraterone selectively and irreversibly inhibits intratumoral androgen biosynthesis by potently blocking CYP17A1. As a result, less ligand is available for AR activation and AR axis signaling. Seviteronel (VT-464) is also an inhibitor of CYP17A1. Seviteronel has also been shown in preclinical models to have direct inhibitor effects on the AR. Enzalutamide is a potent second-generation antiandrogen that antagonizes the AR, prevents AR translocation into the nucleus, and inhibits AR-mediated transcription. Apalutamide (ARN-509) and darolutamide (ODM-201) are also potent, competitive AR inhibitors with similar mechanisms of action to enzalutamide. EPI-506 reduces AR transcriptional activity by inhibiting protein-protein interactions between the AR and its transcriptional co-regulators. JQ1 is a bromodomain inhibitor that limits AR transcriptional ability by targeting its coactivators. Abbreviations: AD, androstenedione; AKR1C3, aldo-keto reductase family 1 member C3; AR, androgen receptor; CYP17A1, cytochrome P450 c17; DHEA, dehydroepiandrosterone; D, dihydrotestosterone; HSP, heat shock protein; HSD3β1, human 3-beta-hydroxysteroid dehydroxynase/delta5-4 isomerase type 1; P, androgen precursors; PSA, prostate-specific antigen; T, testosterone.

Figure 3

AR somatic missense mutations. The main four missense mutations that are focused on in this review all occur in the AR LBD (AR exons 5–8) and include: L702H, H875Y, F877L (previously published as F876L), and T878A (previously published as T877A). Abbreviations: DBD, DNA binding domain; LBD, ligand binding domain; NTD, N-terminal transactivation domain.

Figure 4

Clinically-relevant splice variants. This figure depicts the gene and protein structures for the AR-V7 and AR^v567es splice variants. Alternate splicing of the AR leads to the formation of the constitutively active, and clinically-relevant, AR-V7 and AR^v567es splice variants. AR-V7 is a variant with a cryptic exon 3 instead of exons 4–8. This alternative splicing leads to a protein that has lost the hinge region and LBD. AR^v567es is a variant that contains full sequences of exons 1–4, and exon 8; however, exons 5–7 are skipped. As a result of alternative splicing, a frameshift causes the creation of a premature stop codon in exon 8. Both splice variants are constitutively active proteins that can bind to DNA to promote transcription without the need for ligand binding. Abbreviations: AR^v567es, androgen receptor splice variant with exons 5–7 skipped; AR-V7, androgen receptor splice variant V7; CE3, cryptic exon 3; NTD, N-terminal transactivation domain; S, premature stop codon; UTR, untranslated region.