Androgen receptor targeting drugs in castration-resistant prostate cancer and mechanisms of resistance

Abstract

Reactivated androgen receptor (AR) signaling drives castration-resistant prostate cancer (CRPC). The novel AR targeting drugs abiraterone and enzalutamide have improved survival of CRPC patients. However, resistance to these agents develops and patients ultimately succumb to CRPC. Potential mechanisms of resistance include the following: 1) Expression of AR splice variants, such as the AR-V7 isoform, which lacks the ligand-binding domain; 2) AR missense mutations in the ligand-binding domain, such as F876L and T877A; and 3) Mutation or overexpression of androgen biosynthetic enzymes or glucocorticoid receptor. Several novel agents may overcome resistance mechanisms. Galeterone acts through multiple mechanisms that include degradation of AR protein and is being evaluated in CRPC patients positive for AR-V7. EPI-001 and related compounds inhibit AR splice variants by targeting the N-terminal transactivation domain of AR. Promising therapies and novel biomarkers, such as AR-V7, may lead to improved outcomes for CRPC patients.

Figure 1. The full-length androgen receptor compared with the AR-V7 splice variant

The AR gene is comprised of nine exons. The full length AR protein contains the N-terminal transactivation domain (encoded in exon 1) that is critical for engaging the cellular transcription complex, the DNA binding domain (encoded in exons 2-3) that directs the binding of AR protein to specific DNA sequences, the hinge region (encoded in exon 4) encoding the nuclear translocation signal, and the ligand-binding domain (encoded in exons 5-8) that binds the androgen ligands. The AR-V7 splice variant is produced by alternate splicing of the AR gene that leads to the addition of cryptic exon 3. This leads to premature termination of the AR protein, which results in the loss of the hinge region and LBD and the formation of truncated androgen receptor. AR-V7 is constitutively localized to the nucleus and binds DNA and promotes transcription of target genes without the need for androgen ligands. Therefore, AR-V7 is not inhibited by agents such as abiraterone or enzalutamide that targets the ligand-binding domain of AR. Each number represents the corresponding exon in the AR. Abbreviations: AR-FL, full length androgen receptor; AR-V7, androgen receptor splice variant V7; CE3, cryptic exon 3; DBD, DNA binding domain; LBD, ligand-binding domain; NTD, N-terminal transactivation domain.

Figure 2. Schematic of inhibition of AR signaling axis by AR targeting agents

In CRPC tumor cells, the CYP17A1 enzyme is required for production of testosterone and DHT from precursors. Abiraterone is a selective and irreversible inhibitor of intratumoral androgen biosynthesis by potently blocking CYP17A1-mediated production of testosterone and DHT, which limits the amount of available ligand for AR axis signaling. Enzalutamide is a second generation antiandrogen that binds to the AR LBD and more potently antagonizes the AR than first generation antiandrogens. It also inhibits AR complex-mediated transcription by preventing AR translocation into the cell nucleus and binding to DNA. Galeterone is a novel agent with tri-modal mechanism of action. It is similar to abiraterone because it inhibits CYP17A1 to prevent intratumoral androgen synthesis, but is also similar to enzalutamide because it is an AR antagonist. Additionally, it also degrades the AR and decreases AR protein levels. EPI-001 is a novel AR-targeting agent that reduces AR transcriptional activity. It inhibits transactivation of the AR NTD through inhibition of protein-protein interactions of AR and co-regulators, thereby blocking induction of androgen target genes Abbreviations: AR, androgen receptor; CYP17A1, cytochrome P450 c17; DHT, dihydrotestosterone; DNA, deoxyribonucleic acid; HSP, heat shock protein; LBD, ligand-binding domain; NTD, N-terminal transactivation domain; T, testosterone.