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 1

High pretreatment AR activity is required and sufficient for growth inhibition by SPA.

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High pretreatment AR activity is required and sufficient for growth inhi...
(A) AR, PSA, and MYC protein expression by Western blot of prostate cancer cell lines treated with VEH or SPA for 72 hours. Representative blot of n = 3 independent experiments. (B) AR protein expression by Western blot of LNCaP cells expressing doxycycline-inducible shRNA against AR pretreated with the indicated concentration of doxycycline (doxy) for 72 hours. Representative blot of n = 2 experiments. (C) Viable cell counts of LNCaP-shAR pretreated with indicated concentration of doxycycline for 72 hours then VEH or SPA for 96 hours (n = 3 independent experiments). (D) AR and MYC protein expression by Western blot of LAPC4 expressing empty vector (EV) or AR treated with VEH or SPA for 7 days. Representative blot of n = 3 independent experiments. (E) Viable cell counts of LAPC4-EV and LAPC4-AR cell lines treated with VEH or SPA for 7 days (n = 3 independent experiments). (F) AR and MYC protein expression by Western blot of 22Rv1 cells expressing empty vector (EV) or AR treated with VEH or SPA for 4 days. Representative blot of n = 3 independent experiments. (G) Viable cell counts of 22Rv1-EV and 22Rv1-AR cell lines treated with VEH or SPA for 7 days (n = 3 independent experiments). VEH, vehicle control EtOH 0.01%. SPA, R1881 10nM. (C, E, G) P value by unpaired 2-tailed t test comparing final cell counts. Biological replicates indicated in gray with mean of each independent experiment in color. i-shAR, inducible-short hairpin RNA against AR. For Western blots, vinculin was used as a loading control.