Androgen receptor targeted therapies in castration-resistant prostate cancer: Bench to clinic

Abstract

The androgen receptor is a transcription factor and validated therapeutic target for prostate cancer. Androgen deprivation therapy remains the gold standard treatment, but it is not curative, and eventually the disease will return as lethal castration-resistant prostate cancer. There have been improvements in the therapeutic landscape with new agents approved, such as abiraterone acetate, enzalutamide, sipuleucel-T, cabazitaxel and Ra-223, in the past 5 years. New insight into the mechanisms of resistance to treatments in advanced disease is being and has been elucidated. All current androgen receptor-targeting therapies inhibit the growth of prostate cancer by blocking the ligand-binding domain, where androgen binds to activate the receptor. Persuasive evidence supports the concept that constitutively active androgen receptor splice variants lacking the ligand-binding domain are one of the resistant mechanisms underlying advanced disease. Transcriptional activity of the androgen receptor requires a functional AF-1 region in its N-terminal domain. Preclinical evidence proved that this domain is a druggable target to forecast a potential paradigm shift in the management of advanced prostate cancer. This review presents an overview of androgen receptor-related mechanisms of resistance as well as novel therapeutic agents to overcome resistance that is linked to the expression of androgen receptor splice variants in castration-resistant prostate cancer.

Keywords: EPI-506; androgen receptor; castration-resistant prostate cancer; novel agents; prostate cancer; splice variants.

Figure 1

Progression of prostate cancer to CRPC. Serum PSA levels correlate with disease burden. Localized disease can be cured by radiation therapy or radical prostatectomy. However, recurrent increasing PSA indicates regrowth of cancer. At the androgen‐dependent disease state, ADTs reduce androgen produced by the testes. Ultimately, the disease will progress into a castration‐resistant phenotype. Although there are several therapeutic agents available for CRPC, the cancer inevitably develops resistance to these therapeutic agents.

Figure 2

Domain organization and structure of FL‐AR and AR‐Vs.95 The human AR gene is located at q11‐12 on the X chromosome. FL‐AR has approximately 919 amino acid residues that comprise four distinctive functional domains: NTD, DBD, HR and LBD. Exon 1 encodes the full NTD, exons 2 and 3 encode the DBD, exon 4 encodes HR, and exons 5–8 encode the LBD. The NTD contains an AF‐1 region, and two transcription activation units (TAU1 and TAU5). Tau1 core sequence motif is ₁₇₈LKDIL₁₈₂, whereas Tau5 core motif is ₄₃₅WHTLF_439. Two motifs involved in protein–protein interactions and AR N/C interactions are located in the NTD: FXXLF and WHTLF motifs. A NLS sequence is found in the HR, with part of it extending into the DBD. The LBD contains an AF‐2 region, which androgen binds to induce interaction between AF‐2 with the FXXLF motif of the NTD, resulting in AR N/C interaction. One of the AR‐Vs, AR^v567es, is alternatively spliced to skip exons 5–7 with a missense stop codon in exon 8. AR‐V7 contains exons 1–3, and leads to the addition of a novel cryptic exon 3. Translated protein products, AR^v567es, contain an exon 4 protein coding region (HR), whereas AR‐V7 lacks HR, shown with the variant specific amino acids derived from the alternative splicing events. Some drug‐specific resistance point mutations in AR‐LBD are shown.31, 33, 66, 69, 70

Figure 3

Molecular biology of CRPC. Continued AR transcriptional activity is a major driver of most CRPC. There are several molecular mechanisms proposed to explain the aberrant AR activity despite castrated levels of testosterone. 1: Amplification of the AR gene and overexpression of AR protein, which provide hypersensitivity to low levels of androgen. 2: AR gain‐of‐function mutations that allow the AR to be activated by non‐androgenic steroidal ligands, such as glucocorticoids, and convert anti‐androgens into agonists. 3: Overexpression of AR co‐activators that can enhance androgen‐dependent and also promote ligand‐independent AR transcriptional activities. 4: Androgen‐independent AR transactivation through its NTD, such as cytokine IL‐6, that can stimulate AR transcriptional activity in the absence of androgen. 5: Increased adrenal and/or intratumoral androgen biosynthesis, generating a low, but sufficient, level of androgen to support AR transcriptional activity. 6: AR splice variants with truncated LBD, which have the potential to be constitutively active regardless of the presence of androgen.

Figure 4

Chemical structures of drugs used for hormone therapy. Small molecule inhibitors that block the androgen axis through inhibition of CYP17, competitive inhibition of the AR LBD or the AR NTD.

Figure 5

Conceivable mechanisms of resistance to abiraterone and enzalutamide. There are several molecular mechanisms proposed to explain resistance to abiraterone and enzalutamide: increased intratumoral androgen biosynthesis as a result of upregulation of CYP17 enzymes or a gain‐of‐function mutation (N367T) in 3βHSD1; AR gain‐of‐function mutations that allow the AR to be activated by anti‐androgens; alternative steroid receptors, such as GR or PR activation, to bypass AR; reciprocal feedback regulation of PI3K/Akt/mTOR pathway; neuroendocrine transdifferentiation; and constitutively active AR‐Vs with truncated LBD. Some novel AR‐targeted agents that are in clinical development with potential to overcome resistance are shown.