Androgen receptor activity in prostate cancer dictates efficacy of bipolar androgen therapy through MYC
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
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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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 5

Downregulation of AR drives acquired resistance to SPA.

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Downregulation of AR drives acquired resistance to SPA. (A) Cell cycle a...
(A) Cell cycle analysis by propidium iodide staining of LNCaP cells treated with VEH or SPA. Average values of n = 2 independent experiments. (B) Clonogenic survival of LNCaP cells treated for 26 days with VEH or SPA, followed by 7 days rest without treatment, then treatment with dose of R1881 as indicated. Representative photograph of n = 2 independent experiments. (C–E) AR, KLK3, and MYC mRNA expression by qPCR of LNCaP cells treated with VEH or SPA (n = 3 independent experiments). Ct values were normalized to ACTB for each sample, then to VEH × 5 days, and expressed as median ± SD with P values determined by unpaired 2-tailed t test. (F) AR, PSA, and MYC protein expression by Western blot of LNCaP cells treated with VEH or SPA for 5 or 26 days. Representative blot of n = 3 independent experiments. (G) Chromatin accessibility by ATAC-Seq of the AR promoter (dotted box) of LNCaP cells treated with VEH or SPA for 5 or 26 days (performed in duplicate). (H) AR and MYC protein expression by Western blot of LNCAP-EV and LNCAP-AR cells treated with VEH or SPA for 72 hours. Representative blot of n = 3 independent experiments. (I) Cell cycle analysis by propidium iodide staining of LNCaP-EV and LNCaP-AR cells treated with VEH or SPA. Average values of n = 3 independent experiments. VEH, vehicle control, EtOH 0.01%; SPA, R1881, 10nM; LNCaP-SPAR, LNCaP with acquired resistance to SPA. For Western blots, vinculin was used as a loading control.