Benjamin M. Spector

Background:  Prostate cancer (PC) is the second most common malignancy in males.¹ The vast majority of cases are adenocarcinomas stimulated by androgen receptor (AR) signaling, making androgen deprivation therapy (ADT) the cornerstone of systemic treatment.^2,3 Unfortunately, castration-resistant prostate cancer (CRPC) inevitably develops and many of those cases present with metastatic disease.⁴ Evidence has implicated the glucocorticoid receptor (GR) as an alternative driver of tumor growth when AR signaling is suppressed.⁴ Because AR transcriptionally represses GR, it is possible that loss of AR through various mechanisms may allow GR to function in an abnormal cellular context fueling tumor-promoting transcriptional programs.⁵

Objective:  This review aims to synthesize current evidence on the role of GR in mediating resistance to AR-targeted therapies in CRPC.

Search Methods:  Literature was identified through searches of PubMed and ClinicalTrials.gov from 2017 to 2026 using the following keywords: “castration-resistant prostate cancer”, “glucocorticoid receptor”, and “androgen receptor”.

Results:  Multiple studies have shown that high GR expression was independently associated with advanced tumor stage and early PSA recurrence.⁶ Additionally, studies have shown that AR-null lines unexpectedly retained sensitivity to high-dose enzalutamide, attributed to off-target GR inhibition. Treatment with the selective GR antagonist mifepristone confirmed GR-mediated proliferative signaling in these cells.⁵

At the chromatin level, it was demonstrated that AR activation in androgen-sensitive VCaP cells facilitates GR loading at otherwise inaccessible genomic sites. Furthermore, joint AR/GR activation synergistically induced  genes associated with favorable clinical outcomes, suggesting a tumor-suppressive GR function when AR is intact.⁷ Conversely, it was shown that AR inactivation via enzalutamide treatment upregulates GR and drives its binding to pre-established AR driven enhancers in androgen-dependent cell lines, thus sustaining AR-like transcriptional programs and fueling cancer growth. Interestingly, CRPC cells displayed constitutive GR occupancy at AR sites regardless of treatment.⁸

Clinically, a Phase I trial of enzalutamide combined with the selective GR modulator relacorilant demonstrated tolerability with no dose-limiting toxicities and PSA declines in a subset of patients with metastatic CRPC.⁹

Finally, TBX2, a T-box family of transcription factor (TF) is over-expressed during the progression to CRPC and metastatic CRPC and was identified as a molecular switch that transcriptionally represses AR while upregulating GR through direct promoter binding and protein–protein interactions with GR and LSD1. Disruption of the TBX2–GR complex with the LSD1 inhibitor SP2509 restored enzalutamide sensitivity in CRPC models.¹⁰ This highlights a potential targeted GR inhibition therapy focused on the. ¹⁰

Conclusion:  This review establishes that GR upregulation following AR inhibition is a clinically relevant and mechanistically defined pathway of resistance in CRPC. GR expression functions as both a prognostic biomarker and a therapeutic target, though its activity is heavily context dependent. GR is tumor-suppressive when co-expressed with functional AR, but oncogenic when AR is absent or inhibited due to GR binding and functioning at previously AR driven genes.^7,8 Future research should prioritize biomarker-driven patient selection for GR-targeting strategies, elucidate the efficacy of GR targeted treatment, and the further characterization of the TBX2-GR-LSD1 complex.

Works Cited

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