Androgen receptor activity in prostate cancer dictates efficacy of bipolar androgen therapy through MYC
Laura A. Sena, … , Mark C. Markowski, Samuel R. Denmeade
Laura A. Sena, … , Mark C. Markowski, Samuel R. Denmeade
Published October 4, 2022
Citation Information: J Clin Invest. 2022;132(23):e162396. https://doi.org/10.1172/JCI162396.
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Research Article Oncology

Androgen receptor activity in prostate cancer dictates efficacy of bipolar androgen therapy through MYC

Abstract

Testosterone is the canonical growth factor of prostate cancer but can paradoxically suppress its growth when present at supraphysiological levels. We have previously demonstrated that the cyclical administration of supraphysiological androgen (SPA), termed bipolar androgen therapy (BAT), can result in tumor regression and clinical benefit for patients with castration-resistant prostate cancer. However, predictors and mechanisms of response and resistance have been ill defined. Here, we show that growth inhibition of prostate cancer models by SPA required high androgen receptor (AR) activity and were driven in part by downregulation of MYC. Using matched sequential patient biopsies, we show that high pretreatment AR activity predicted downregulation of MYC, improved clinical response, and prolonged progression-free and overall survival for patients on BAT. BAT induced strong downregulation of AR in all patients, which is shown to be a primary mechanism of acquired resistance to SPA. Acquired resistance was overcome by alternating SPA with the AR inhibitor enzalutamide, which induced adaptive upregulation of AR and resensitized prostate cancer to SPA. This work identifies high AR activity as a predictive biomarker of response to BAT and supports a treatment paradigm for prostate cancer involving alternating between AR inhibition and activation.

Authors

Laura A. Sena, Rajendra Kumar, David E. Sanin, Elizabeth A. Thompson, D. Marc Rosen, Susan L. Dalrymple, Lizamma Antony, Yuhan Yang, Carolina Gomes-Alexandre, Jessica L. Hicks, Tracy Jones, Kiara A. Bowers, Jillian N. Eskra, Jennifer Meyers, Anuj Gupta, Alyza Skaist, Srinivasan Yegnasubramanian, Jun Luo, W. Nathaniel Brennen, Sushant K. Kachhap, Emmanuel S. Antonarakis, Angelo M. De Marzo, John T. Isaacs, Mark C. Markowski, Samuel R. Denmeade

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Figure 2

High pretreatment AR activity is required for downregulation of MYC by SPA, which contributes to growth inhibition.

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High pretreatment AR activity is required for downregulation of MYC by S...
(A) MYC mRNA expression by quantitative PCR (qPCR) of prostate cancer cell lines treated with VEH or SPA for 72 hours (n = 3 independent experiments). Ct value was first normalized to ACTB for each sample, then to VEH for each cell line, and expressed as mean ± SD with P values were determined by unpaired 2-tailed t test with Welch correction for unequal variances. (B) MYC protein expression by Western blot of LNCaP cells expressing doxycycline-inducible shRNA against AR pretreated with indicated concentration of doxycycline (doxy) for 72 hours then VEH or SPA for 96 hours. Representative blot of n = 2 experiments. (C) AR and MYC protein expression by Western blot of LNCaP-empty vector (LNCaP-EV) and LNCaP-MYC cell lines treated with VEH or SPA for 72 hours. Representative blot of n = 3 independent experiments. (D) Viable cell counts of LNCaP-EV and LNCaP-MYC cell lines treated with VEH or SPA for 7 days (n = 3 independent experiments). P value was determined by unpaired 2-tailed t test. Biological replicates are indicated in gray with the mean of each independent experiment in color. (E) AR and MYC expression by Western blot of LAPC4-EV, LAPC4-AR, and LAPC4-AR-MYC cell lines treated with VEH or SPA for 7 days. Representative blot of n = 3 independent experiments. (F) Viable cell counts of LAPC4-EV, LAPC4-AR, and LAPC4-AR-MYC cell lines treated with VEH or SPA for 7 days (n = 3 independent experiments). P value was determined by unpaired 2-tailed t test. Biological replicates indicated in gray with the mean of each independent experiment in color. VEH, vehicle control, EtOH 0.01%. SPA, R1881, 10nM. For Western blots, vinculin was used as a loading control.