Androgen receptor (AR) heterogeneity in prostate cancer and therapy resistance

Abstract

Androgen receptor (AR), a ligand-dependent nuclear transcription factor and a member of steroid hormone receptor family, plays an important role in prostate organogenesis by regulating epithelial differentiation and restricting cell proliferation. Although rarely mutated or amplified in treatment-naïve prostate cancer (PCa), AR signaling drives tumor growth and as a result, therapies that aim to inhibit AR signaling, called ARSIs (AR signaling inhibitors), have been in clinical use for >70 years. Unfortunately, the clinical efficacy of ARSIs is short-lived and the majority of treated patients develop castration-resistant PCa (CRPC). Numerous molecular mechanisms have been proposed for castration resistance; however, the cellular basis for CRPC emergence has remained obscure. One under-appreciated cellular mechanism for CRPC development is the AR heterogeneity that pre-exists in treatment-naive primary tumors, i.e., although most PCa cells express AR (i.e., AR⁺), there is always a population of PCa cells that express no/low AR (i.e., AR^-/lo). Importantly, this AR heterogeneity becomes accentuated during ARSI treatment and highly prominent in established CRPC. Here, we provide a succinct summary of AR heterogeneity across the PCa continuum and discuss its impact on PCa response to treatments. While AR⁺ PCa cells/clones exhibit exquisite sensitivities to ARSIs, AR^-/lo PCa cells/clones, which are greatly enriched in stem cell signaling pathways, display de novo resistance to ARSIs. Finally, we offer several potential combinatorial strategies, e.g., ARSIs with stem cell targeting therapeutics, to co-target both AR⁺ and AR^-/lo PCa cells and metastatic clones.

Keywords: Androgen receptor; Cancer cell heterogeneity; Cancer stem cells; Castration-resistant prostate cancer; Prostate cancer; Therapy resistance.

Fig. 1.. Domain structure of human AR and its subcellular mobilization.

(A) The protein domain structure of human AR. AR is a protein of 919 amino acids (aa) consisting of several functional domains including N-terminal domain (NTD), DNA binding domain (DBD) and ligand binding domain (LBD) at the C-terminus. Also depicted are the FXXLF motif at aa 23–27, the WXXLF motif at aa 453–457, the nuclear localization signal (NLS) and a putative mitochondrial localization signal (MLS). (B) Pipelines and methods used to curate putative AR-interacting proteins. A total of 513 AR-interacting partners were identified using McGill/HPRAD/Bio-Grid databases as well as extensive literature search and curation (also see Table S1). Note that the AR-interacting proteins encompass those that physically interact with AR (either directly with AR or indirectly through other proteins) as well as those that functionally interact and interface with AR (signaling) but without any physical interactions. (C) Categorization of AR-interacting partners via their functions and subcellular localizations. The heatmap, generated using Morpheus (a Broad Institute’s web-based heatmap builder), presents the 513 AR-interacting proteins according to their potential involvement in the indicated biological processes (x-axis) and subcellular localizations (y-axis). The heatmap legend indicates the relative probability (%) of AR-interacting partners of falling into a specific functional category. For instance, the upper left box with 84 indicates that 84 AR-interacting proteins in the nucleus function, with 60–80% probability (certainty), in ‘Transcriptional regulation’. On the other hand, the upper right box with 1 indicates that 1 AR-interacting protein in the nucleus functions, with 20–40% probability, in ‘Protein synthesis’. Nuc (nucleus), Cyto (cytosol), PM (Plasma membrane), Golgi (Golgi apparatus), ER (endoplasmic reticulum), Mito (mitochondria), CSK (cytoskeleton), Z-line (the dark band in each myofibril where actin and myosin filaments overlap), CJ (cell junction), EC (extracellular), ECM (extracellular matrix). (D) Pie chart (%) presentation of the 513 AR-interacting proteins according to their subcellular localizations.

Fig 2.. Potential therapeutic strategies to target PCa cell heterogeneity and plasticity.

(A) Combinatorial strategies in the mCRPC setting. (B) Combinatorial strategies in the primary PCa setting. Please see Text for discussions. Note that the AR^−/lo PCa cell populations in treatment-naïve tumors (left) vs. ADT-treated and CRPC (right) will likely possess different transcriptomic profiles and epigenetic landscapes despite that they share similarities in phenotype and therapy resistance [13,36]. Also, the cartoon (adapted from ref. with permission) was not intended to imply that the AR^+/hi and AR^−/lo cell populations in mCRPC are directly derived from the AR⁺ and AR^−/lo cell populations in treatment-naïve primary tumors, respectively. This is because ADT-induced cancer cell plasticity may inter-convert the two cell populations, but the proposed combinatorial strategies may simultaneously target both PCa cell heterogeneity and plasticity in established CRPC (A) or significantly delay and inhibit the emergence of CRPC when used to treat primary tumors (B).