Resistance to second generation antiandrogens in prostate cancer: pathways and mechanisms

Abstract

Androgen deprivation therapy targeting the androgens/androgen receptor (AR) signaling continues to be the mainstay treatment of advanced-stage prostate cancer. The use of second-generation antiandrogens, such as abiraterone acetate and enzalutamide, has improved the survival of prostate cancer patients; however, a majority of these patients progress to castration-resistant prostate cancer (CRPC). The mechanisms of resistance to antiandrogen treatments are complex, including specific mutations, alternative splicing, and amplification of oncogenic proteins resulting in dysregulation of various signaling pathways. In this review, we focus on the major mechanisms of acquired resistance to second generation antiandrogens, including AR-dependent and AR-independent resistance mechanisms as well as other resistance mechanisms leading to CRPC emergence. Evolving knowledge of resistance mechanisms to AR targeted treatments will lead to additional research on designing more effective therapies for advanced-stage prostate cancer.

Keywords: Prostate cancer; androgen receptor; castration resistance prostate cancer; second-generation antiandrogens.

Figure 1

The androgen-androgen receptor signaling pathway. A: The androgen receptor gene resides on the long arm of X chromosome (locus Xq11-Xq12). Upon transcription it produces mRNA containing 8 exons interrupted by introns which codes for the AR protein made up of 919 amino acids. AR protein contains several functional domains such as N-terminal domain (NTD), DNA binding domain (DBD) and ligand binding domain (LBD); B: Ligand binding domain of androgen receptor in complex with its ligand 5-α-dihydrotestosterone (5ADHT). The crystal structure of the androgen receptor ligand binding domain in complex with 5-alpha dihydrotestosterone (PDB ID 1T7T with resolution 1.70Å) was downloaded from RCSB protein databank. The PyMOL molecular visualization system was used to represent the protein-ligand complex in cartoon-sticks form; C: General mechanism of AR signaling. Testosterone diffuses into the cells and gets converted into dihydrotestosterone (DHT) via the action 5-α-reductase (5-a-R). DHT binds to the ligand binding pocket of androgen receptor (AR) and promotes its dissociation from the heat shock protein (HSP). Free AR then translocate into the nucleus and binds to androgen receptor element (ARE) present in the promoter region of AR responsive genes. At the promoter AR recruits components of basal transcriptional machinery such as TATA binding protein (TBP), transcription factor IIF (TFIIF), and cAMP responsive element binding protein (CRBP) which ensures the transcription of AR responsive genes

Figure 2

Distinct gene expression pattern of LNCaP-enzalutamide resistant cells in relation to AR. LNCaP cells treated with antiandrogen enzalutamide to generate LNCaP-enzalutamide resistant cells. These resistant cells show distinct gene expressed pattern in relation of AR in nucleus, cytoplasm, plasma membrane, and extracellular space. The red color shows increased expression, pink color shows less expression whereas green color shows decreased expression. The blue arrowhead shows genes leads to inhibition, while orange color shows gene leads to activation, while the dotted line shows its indirect interaction. AR: androgen receptor

Figure 3

Cascade of upstream and downstream transcriptional regulators. The NGS data of LNCaP-enzalutamide resistant cells identified (A) upstream and (B) downstream regulators, based on overlap p-values computed based on significant overlap between genes in the dataset and known targets regulated by the transcriptional regulator and represented in graph on scale of expression log ratio at overlap P-value ≤ 0.001. NGS: next generation sequencing

Figure 4

Mechanisms of enzalutamide and abiraterone acetate resistance in prostate cancer cells. Aberrant activation of PI3K/Akt pathway overexpressing p110β with loss of PTEN gene. Interaction of p85α subunits with Src kinase activates MAPK. Activated Akt overexpresses N-Myc, FOXO, ONECUT2 and EZH2 leads to activation of HIF1α, SMAD3, SOX2, and Nanog through suppressing TP53 and RB1. AR in the presence of hnRPA-1 forms AR-Vs and activates NF-κB signaling which in turn up-regulates IL-6 gene expression. Long-term exposure to antiandrogens significantly increases GR expression. Interaction of aberrant β-catenin of Wnt signaling to AR leads to expression target genes involved prostate cancer cell proliferation, tumor growth, stem cell marker expression, and chemotherapy drug resistance. Interaction of these genes with each other and with AR promotes enzalutamide/abiraterone acetate mediated neuroendocrine prostate cancer (NEPC) and castration resistant prostate cancer (CRPC) formation. PI3K: phosphatidylinositol-3 kinase; PTEN: phosphatase and tensin homolog; MAPK: mitogen-activated protein kinase; EZH2: enhancer of zeste homolog 2; HIF1α: hypoxia-inducible factors- α; SOX2: SRY-box transcription factor 2; TP53: tumor protein 53; RB1: retinoblastoma1; hnRPA-1: heterogeneous nuclear ribonucleoprotein A1; IL-6: interleukin-6; AR-vs: Androgen receptor variants; AR: androgen receptor; GR: glucocorticoid receptor; CRPC: castration resistant prostate cancer; NEPC: neuroendocrine prostate cancer; BCAF: B-cell activating factor; LT: Lymphotoxin-β; AURKA: Aurora kinase A