Monitoring Glucocorticoid Receptor in Plasma-derived Extracellular Vesicles as a Marker of Resistance to Androgen Receptor Signaling Inhibition in Prostate Cancer.

Abstract

Disease progression following androgen ablation was shown to be associated with upregulation of the glucocorticoid receptor (GR). Longitudinal monitoring of GR expression in circulating extracellular vesicles (EV) may reflect changes in the tumor cell and facilitates detection of acquired resistance. We utilized LNCaP, LREX cells and a patient-derived xenograft, MDA PDX 322-2-6a, for in vitro and in vivo experiments. Plasma-derived EVs were isolated from patients with localized high-risk prostate cancer undergoing androgen ablation. The mRNA levels of GR in EVs and their responsive genes were detected by transcriptome analysis, qRT-PCR and the protein levels by Western blot analysis. We detected changes in GR expression at mRNA and protein levels in EVs derived from LNCaP and LREX cells in in vitro studies. In in vivo experiments, LNCaP and the PDX MDA 322-2-6a-bearing mice were treated with enzalutamide. GR levels in plasma-derived EVs were increased only in those tumors that did not respond to enzalutamide. Treatment of mice bearing enzalutamide-resistant tumors with a GR inhibitor in combination with enzalutamide led to a transient pause in tumor growth in a subset of tumors and decreased GR levels intracellular and in plasma-derived EVs. In a subgroup of patients with high-risk localized prostate cancer treated with androgen signaling inhibition, GR was found upregulated in matching tissue and plasma EVs. These analyses showed that GR levels in plasma-derived EVs may be used for monitoring the transition of GR expression allowing for early detection of resistance to androgen ablation treatment.

SIGNIFICANCE:

Longitudinal monitoring of GR expression in plasma-derived EVs from patients with prostate cancer treated with androgen signaling inhibitors facilitates early detection of acquisition of resistance to androgen receptor signaling inhibition in individual patients.

• Authors: Emanuela Gentile, Andrew W Hahn, Jian H Song, Anh Hoang, Peter D A Shepherd, Sumankalai Ramachandran, Nora M Navone, Eleni Efstathiou, Mark Titus, Paul G Corn, Sue-Hwa Lin, Christopher J Logothetis, Theocharis Panaretakis
• Journal: Cancer research communications (Cancer Res Commun) Vol. 3 Issue 12 Pg. 2531-2543 (12 13 2023) ISSN: 2767-9764 [Electronic] United States
• PMID: 37930121 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: © 2023 The Authors; Published by the American Association for Cancer Research.

Chemical References

• Receptors, Glucocorticoid
• Biomarkers
• enzalutamide
• Phenylthiohydantoin
• Antineoplastic Agents
• Mifepristone

Topics

• Receptors, Glucocorticoid (blood, genetics)
• Extracellular Vesicles (metabolism)
• Biomarkers (blood)
• Signal Transduction
• Humans
• Animals
• Mice
• Male
• Cell Line, Tumor
• Phenylthiohydantoin (pharmacology)
• Antineoplastic Agents (pharmacology)
• Drug Resistance, Neoplasm (drug effects)
• Gene Expression Regulation (drug effects)
• Prostatic Neoplasms (diagnosis, drug therapy, genetics)
• Mifepristone (pharmacology)