Abstract
GR is activated in response to AR inhibition and confers resistance to second-generation antiandrogens.
Major finding: GR is activated in response to AR inhibition and confers resistance to second-generation antiandrogens.
Clinical relevance: Corticosteroid therapy might promote prostate cancer progression in certain contexts.
Impact: Combining specific GR antagonists with second-generation antiandrogens could prolong responses.
Second-generation antiandrogens such as enzalutamide and ARN-509 restore androgen receptor (AR) inhibition and prolong survival in castration-resistant prostate cancer (CRPC), but acquired resistance usually develops within a year. AR mutations have been found to confer resistance to second-generation antiandrogens but have only been identified in a small number of patients with progressive disease. To identify other potentially more prevalent mechanisms of resistance to antiandrogens, Arora and colleagues continuously treated tumor-bearing mice with enzalutamide or ARN-509 and analyzed gene expression in tumors that progressed after long-term treatment. One of the most highly upregulated genes in resistant tumors was NR3C1, which encodes the glucocorticoid receptor (GR), and GR protein levels were significantly higher in drug-resistant tumors than in tumors from vehicle-treated mice. Knockdown or inhibition of GR suppressed enzalutamide-resistant growth of GR-overexpressing prostate cancer cells, and glucocorticoid-induced activation of GR was sufficient to induce resistance in enzalutamide-sensitive cells, indicating that GR activation plays a direct role in antiandrogen resistance. Transcriptional profiling and chromatin immunoprecipitation sequencing showed that GR occupied a significant proportion of AR binding sites in enzalutamide-resistant cells and transcriptionally activated a subset of AR target genes in an AR-independent manner, supporting a model in which activation of another nuclear receptor can bypass AR blockade and promote antiandrogen resistance by replacing AR activity. Importantly, in patients with metastatic CRPC receiving enzalutamide therapy, significantly more GR-positive cells were found in bone metastases of patients with poor responses than in patients who responded to therapy for more than 6 months, suggesting that GR activation may be a prevalent mechanism of acquired antiandrogen resistance in the clinical setting. These findings suggest that combined inhibition of GR and AR could lead to more durable responses to second-generation antiandrogens and that corticosteroid therapy may be contraindicated in patients with prostate cancer.
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