Emerging mechanisms of resistance to androgen receptor inhibitors in prostate cancer

Abstract

During the past 10 years, preclinical studies implicating sustained androgen receptor (AR) signalling as the primary driver of castration-resistant prostate cancer (CRPC) have led to the development of novel agents targeting the AR pathway that are now in widespread clinical use. These drugs prolong the survival of patients with late-stage prostate cancer but are not curative. In this Review, we highlight emerging mechanisms of acquired resistance to these contemporary therapies, which fall into the three broad categories of restored AR signalling, AR bypass signalling and complete AR independence. This diverse range of resistance mechanisms presents new challenges for long-term disease control, which may be addressable through early use of combination therapies guided by recent insights from genomic landscape studies of CRPC.

Figure 1. AR signaling is regulated by the hypothalamic-pituitary-testicular axis, adrenal gland steroidogenesis and prostate cell intrinsic factors

A. The hormones gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH) bind to their cognate receptors, resulting in testosterone secretion from Leydig cells of the testes. Chronic use of GnRH agonists leads to downregulation of the GnRH receptor (GnRH-R) while antagonists provide immediate GnRH-R blockade. Both agents suppress LH production causing a decline in serum testosterone to castrate levels. The adrenal glands secrete androgens dehydroepiandrosterone (-sulfate) (DHEA-S, predominantly), DHEA and androstenedione (AD) into the circulation. B. Adrenal androgen de novo steroidogenesis (enzymes in ovals). CYP17A has 17α-hydroxylation (red) and 17, 20-lyase (blue) activities; both inhibited by abiraterone. Dashed arrow indicates a weak effect. C. Prostate conversion of adrenal androgens to dihydrotestosterone (DHT). DHT binds to androgen receptor (AR) in the cytoplasm, triggering a conformational change leading to nuclear translocation ^, . DHT bound AR homodimerizes and with coactivators (CoA) and RNA polymerase II (RNA Pol II) or corepressors (not shown), binds DNA at cis androgen response elements to activate (shown) or repress AR target gene expression, respectively ^–. Enzalutamide inhibits AR by competing with DHT for binding, blocking nuclear translocation, and blocking DNA and cofactor binding .

Figure 2. Overview of resistance mechanisms to next generation AR targeted therapies for CRPC

A. Increasing disease burden following primary prostate cancer therapy is indicated by rising prostate specific antigen (PSA) and/or radiographic progression and is treated with medical castration. The castration resistant prostate cancer (CRPC) stage follows failure of castration therapy. Next generation androgen receptor (AR) inhibitors (abiraterone, enzalutamide) are initiated during CRPC, but acquired (or inherent) resistance mechanisms lead to disease recurrence and ultimately death. B. Heterogeneous patterns of resistance mechanisms to AR inhibitors include broad classes of restored AR signaling, AR bypass signaling, and complete AR independence. The majority of patients relapse with typical AR-positive adenocarcinoma with rising PSA levels. Although the incidence is not precisely defined, a subset of relapsing patients present with AR-low or negative tumors and low PSA. The histological classification of these cancers is an area of active investigation, but include classical small cell carcinoma (SCC), neuroendocrine prostate cancer (NEPC) in the absence of SCC-histological features, and potentially emerging, novel subtypes. Known or suspected molecular drivers of resistance are highlighted. Note that these molecular alterations are not mutually exclusive to each class, and some degree of overlap occurs in model systems and is likely in patients. AURKA, Aurora kinase A, DHT, dihydrotestosterone, GR, glucocorticoid receptor.

Figure 3. Domain structure of AR, cancer associated missense mutations, and splice variants

A. Androgen receptor (AR) is 920 amino acids long and consists of four functional domains encoded by eight exons: the ligand independent amino terminal transactivation domain (NTD, exon 1), DNA binding domain (DBD, exons 2–3), the hinge region (exon 4), and the ligand binding domain (LBD, exons 4–8). Note that exon 4 comprises both the hinge region and part of the LBD. The nuclear localization signal (NLS, pair of green bars) of AR is a bipartite motif contained within exons 3 and 4. Recurring missense mutations are noted beneath the AR schematic. These same mutations are also described in the literature with alternative numerical designations based on earlier genomic builds (that is, L701H, W741C, H874Y, T877A and originally published as T868A). B. The protein structures of representative androgen receptor splice variants (ARVs) are shown with the in-frame variant specific amino acids derived from the alternative splicing events.

Figure 4. Opposing roles of glucocorticoids in prostate cancer

A. Glucocorticoids (GCs) negatively regulate adrenocorticotropic hormone (ACTH) production from the pituitary gland, which in turn diminishes adrenal androgen production. As a consequence, there is less conversion of adrenal androgens to dihydrotestosterone (DHT). This effect is observed clinically in some patients receiving exogenous GCs (such as prednisone, dexamethasone) by decline in androgen receptor (AR) activity as measured by prostate specific antigen (PSA) ^, . B. In other situations, GCs can directly stimulate tumor proliferation by activating AR target gene expression. One scenario is through outcompeting enzalutamide for binding to AR target genes in tumor clones carrying the AR^L702H mutation, which is stimulated by GC. Another route is GC activation of tumors by direct activation of glucocorticoid receptor (GR) in tumors that acquire GR expression, thereby bypassing the blockage of AR target gene expression by enzalutamide.