Supraphysiological androgens suppress prostate cancer growth through androgen receptor–mediated DNA damage
Payel Chatterjee, … , Samuel R. Denmeade, Peter S. Nelson
Payel Chatterjee, … , Samuel R. Denmeade, Peter S. Nelson
Published October 1, 2019; First published July 16, 2019
Citation Information: J Clin Invest. 2019;129(10):4245-4260. https://doi.org/10.1172/JCI127613.
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Research Article Endocrinology Oncology

Supraphysiological androgens suppress prostate cancer growth through androgen receptor–mediated DNA damage

Abstract

Prostate cancer (PC) initially depends on androgen receptor (AR) signaling for survival and growth. Therapeutics designed to suppress AR activity serve as the primary intervention for advanced disease. However, supraphysiological androgen (SPA) concentrations can produce paradoxical responses leading to PC growth inhibition. We sought to discern the mechanisms by which SPA inhibits PC and to determine if molecular context associates with antitumor activity. SPA produced an AR-mediated, dose-dependent induction of DNA double-strand breaks, G0/G1 cell-cycle arrest, and cellular senescence. SPA repressed genes involved in DNA repair and delayed the restoration of damaged DNA, which was augmented by poly (ADP-ribose) polymerase 1 inhibition. SPA-induced double-strand breaks were accentuated in BRCA2-deficient patients with PC, and combining SPA with poly (ADP-ribose) polymerase or DNA-dependent protein kinase inhibition further repressed growth. Next-generation sequencing was performed on biospecimens from patients with PC receiving SPA as part of ongoing phase II clinical trials. Patients with mutations in genes mediating homology-directed DNA repair were more likely to exhibit clinical responses to SPA. These results provide a mechanistic rationale for directing SPA therapy to patients with PC who have AR amplification or DNA repair deficiency and for combining SPA therapy with poly (ADP-ribose) polymerase inhibition.

Authors

Payel Chatterjee, Michael T. Schweizer, Jared M. Lucas, Ilsa Coleman, Michael D. Nyquist, Sander B. Frank, Robin Tharakan, Elahe Mostaghel, Jun Luo, Colin C. Pritchard, Hung-Ming Lam, Eva Corey, Emmanuel S. Antonarakis, Samuel R. Denmeade, Peter S. Nelson

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Figure 1

Supraphysiological androgen concentrations promote DNA damage and enhance AR transcriptional output.

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Supraphysiological androgen concentrations promote DNA damage and enhanc...
(A) qRT-PCR quantitation of AR transcript levels (n = 5). (B) Confocal immunostaining of γH2AX in LNCaP and LNCaPAR cells in normal growth medium, control medium (Ct), or 24 hours after treatment with 1 nM or 10 nM R1881. (C) Quantitation of γH2AX foci in all cell lines exposed to 1 nM and 10 nM R1881. Average number of foci were plotted by calculating the mean FPC from different fields. (D) Quantitation of γH2AX foci measured in LNCaP and LNCaPAR cells at time intervals following exposure to 10 nM R1881. (E) Immunofluorescence analysis of AR S81 phosphorylation in LNCaP cells in control medium (Ct) or 10 nM 1881. (F) Quantitation of AR S81 foci in LNCaP and LNCaPAR cells. (G) Transcript levels of KLK3, NKX3.1, and TMPRSS2 in LNCaP cells following exposure to R881 concentrations 0.01–100 nM. In C, D and F, data represent the mean ± SD (n = 3 replicates per experiment). Original magnification for B and E: ×40. **P < 0.01 by 2-way ANOVA.