Aberrant corticosteroid metabolism in tumor cells enables GR takeover in enzalutamide resistant prostate cancer

• DOI: 10.7554/elife.20183
• Publication Date: 2017-02-13T00:00:09Z
• Authors: Jianneng Li; Mohammad Alyamani; Ao Zhang; Kai-Hsiung Chang; Michael Berk; Zhenfei Li; Ziqi Zhu; Marianne Petro; Cristina Magi-Gal...; Mary-Ellen Taplin; Jorge A Garcia; Kevin Courtney; Eric A Klein; Nima Sharifi
• Keywords: Enzalutamide; Antiglucocorticoid

Prostate cancer is driven by androgen stimulation of the receptor (AR). The next-generation AR antagonist, enzalutamide, prolongs survival, but resistance and lethal disease eventually prevail. Emerging data suggest that glucocorticoid (GR) upregulated in this context, stimulating expression AR-target genes permit continued growth despite blockade. However, countering mechanism administration GR antagonists problematic because essential for life. We show enzalutamide treatment human models prostate patient tissues accompanied a ubiquitin E3-ligase, AMFR, mediating loss 11β-hydroxysteroid dehydrogenase-2 (11β-HSD2), which otherwise inactivates cortisol, sustaining tumor cortisol concentrations to stimulate resistance. Remarkably, reinstatement 11β-HSD2 expression, or AMFR loss, reverses mouse xenograft tumors. Together, these findings reveal surprising metabolic may be targeted with strategy circumvents requirement systemic ablation.