Glucocorticoid Receptor Confers Resistance to Anti-Androgens by Bypassing Androgen Receptor Blockade

By V. Arora, E. Schenkein, R. Murali, S. Subudhi, John Wongvipat, M. Balbas, Neel Shah, Ling Cai, E. Efstathiou, C. Logothetis and 2 more. Cell, 2013

932 citations recorded by the source corpus.

Summary The treatment of advanced prostate cancer has been transformed by novel antiandrogen therapies such as enzalutamide. Here we identify induction of glucocorticoid receptor (GR) expression as a common feature of drug resistant tumors in a credentialed preclinical model, a finding also confirmed in patient samples. GR substituted for the androgen receptor (AR) to activate a similar but distinguishable set of target genes and was necessary for maintenance of the resistant phenotype. The GR agonist dexamethasone was sufficient to confer enzalutamide resistance whereas a GR antagonist restored sensitivity. Acute AR inhibition resulted in GR upregulation in a subset of prostate cancer cells due to relief of AR-mediated feedback repression of GR expression. These findings establish a novel mechanism of escape from AR blockade through expansion of cells primed to drive AR target genes via an alternative nuclear receptor upon drug exposure.

Subfields: Genetics, Pharmacology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/469cdc82856a40eeff272b02be60b842da5a3ac3

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Genetics

1. Brent R. Stockwell
2. R. DePinho

In Pulmonary and Respiratory Medicine

1. Brent R. Stockwell
2. Deguang Liang
3. R. Vessella
4. Scott J. Dixon
5. D. Tang
6. R. Kang
7. M. Conrad

Citations in the corpus

• Genetics and biology of prostate cancer (2018, background): “Glucocorticoid receptor (GR)-dependent castration resistance Up-regulation of the GR can cross-regulate AR target genes to confer resistance to enzalutamide or ARN-509 (Arora et al. 2013).”
• Organoid cultures derived from patients with advanced prostate cancer (2014, neutral): “CRPC tumor cells may remain dependent on AR or AR-like activity, or they may dedifferentiate into AR-independent cells (Arora et al., 2013; Balbas et al., 2013; Beltran et al., 2011; Carver et al., 2011; Chen et al., 2013).”
• RNA-Seq of Single Prostate CTCs Implicates Noncanonical Wnt Signaling in Antiandrogen Resistance (2015, neutral): “Finally, we tested the contribution of ncWnt to antiandrogen resistance in an independent dataset, interrogating the previously published mouse LNCAP xenograft model, in which aberrant activation of GR contributes to enzalutamide resistance (28).”
• Ferroptosis surveillance independent of GPX4 and differentially regulated by sex hormones (2023, background): “An LnAR subline termed LREX0 acquired resistance to ENZ in a GRdependent manner.(42) Interestingly, a subset of AR target genes are still responsive to AR signaling in LREXʹ cells, and we found that ENZ almost completely blocked MBOAT2 expression in these cells (Figure S5O).”
• Androgen Receptor Pathway-Independent Prostate Cancer Is Sustained through FGF Signaling (2017, background): “We also found no evidence of upregulation of the glucocorticoid receptor (GR/NR3C1), a nuclear hormone receptor previously shown to bypass AR requirements (Arora et al., 2013) (Figure 3D).”