Androgen Receptor-Dependent Mechanisms Mediating Drug Resistance in Prostate Cancer

Abstract

Androgen receptor (AR) is a main driver of prostate cancer (PCa) growth and progression as well as the key drug target. Appropriate PCa treatments differ depending on the stage of cancer at diagnosis. Although androgen deprivation therapy (ADT) of PCa is initially effective, eventually tumors develop resistance to the drug within 2-3 years of treatment onset leading to castration resistant PCa (CRPC). Castration resistance is usually mediated by reactivation of AR signaling. Eventually, PCa develops additional resistance towards treatment with AR antagonists that occur regularly, also mostly due to bypass mechanisms that activate AR signaling. This tumor evolution with selection upon therapy is presumably based on a high degree of tumor heterogenicity and plasticity that allows PCa cells to proliferate and develop adaptive signaling to the treatment and evolve pathways in therapy resistance, including resistance to chemotherapy. The therapy-resistant PCa phenotype is associated with more aggressiveness and increased metastatic ability. By far, drug resistance remains a major cause of PCa treatment failure and lethality. In this review, various acquired and intrinsic mechanisms that are AR‑dependent and contribute to PCa drug resistance will be discussed.

Keywords: AR antagonists; androgen deprivation therapy; androgen receptor; castration resistant PCa; prostate cancer.

Figure 1

Schematic view of prostate cancer tumor evolution upon therapy. In general, due to accumulation of mutations, a tumor is composed of many cancer cell types leading to tumor cell heterogeneity. Cancer consists also of cancer stem cells (stem) and other non-cancerous cells (other, including cancer -associated fibroblasts and immune cells). Androgen-deprivation therapy (ADT) is mostly successful inhibiting the growth of androgen-sensitive PCa cells. However, castration-resistant cells may be selected by the treatment and accumulate. Treatment with AR antagonists and other therapeutic drugs, including chemotherapy and radiation, might select for drug resistant PCa cells leading to a more aggressive tumor (such as NEPC). Associated with the tumor evolution, during tumorigenesis PCa develops a variety of androgen bypass signaling.

Figure 2

Summary of some adaptive AR signaling pathways active in DRPC. Androgens and AR-antagonists (Anti) diffuse into PCa cells. Androgens bind and activate the androgen receptor (AR) in the cytoplasm. The AR dissociates from HSP, forms a dimer and translocates into the nucleus. Antagonists inhibit androgen-activated AR by various biochemical mechanisms and block activation of AR signaling. At chromatin, co-regulators such as pioneering factors, co-activators and co-repressors modulate transcriptional activity of AR at androgen response elements (ARE). Adaptive signaling that lead to CRPC includes the upregulation of glucocorticoid receptor (GR) that can bind to AREs and can activate AR signaling despite AR inhibition. Through autocrine signaling IL-6 activates STAT3 that in turn phosphorylates AR and thereby enhancing AR-mediated transactivation. The second-generation AR antagonist Enzalutamide (Enz) increases the expression of AR-V7 variant associated with aggressive PCa and dimerizes with AR to change AR transcriptome landscape. Activation of Src kinase phosphorylates AR and AKT. Both Src and AKT interact with AR and phosphorylate AR to enhance its nuclear translocation. Additionally, Src kinase inhibits LCoR and thereby inactivating its function as co-repressor of AR. Low expression of miRNA-205/-31 stabilizes AR protein and blocks apoptosis. Phosphorylated ACK1/AR complex phosphorylates chromatin and increases accessibility to target genes. PTEN loss results in active PI3K/AKT signaling. Active AKT phosphorylates AR and N-myc. Phosphorylated AR translocates to the nucleus and induces expression of ARE. N-Myc represses AR gene expression. AKT inhibition blocks repression of FOXO by AKT. Hence, FOXO is active and induces expression of genes such as AR and HER3. Inhibition of AR by anti-androgens downregulates FKBP5 expression. Therefore, FKBP5 cannot act as a chaperone of PHLPP leading to the hyperphosphorylation of AKT. AR inhibition by AR further induces pro-survival autophagy. CREB5 forms a complex with AR, resulting into expression of genes involved in oncogenic pathways.