Selective androgen receptor modulators activate the canonical prostate cancer androgen receptor program and repress cancer growth
Michael D. Nyquist, … , Elahe A. Mostaghel, Peter S. Nelson
Michael D. Nyquist, … , Elahe A. Mostaghel, Peter S. Nelson
Published May 17, 2021
Citation Information: J Clin Invest. 2021;131(10):e146777. https://doi.org/10.1172/JCI146777.
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Research Article Oncology

Selective androgen receptor modulators activate the canonical prostate cancer androgen receptor program and repress cancer growth

Abstract

Prostate cancer (PC) is driven by androgen receptor (AR) activity, a master regulator of prostate development and homeostasis. Frontline therapies for metastatic PC deprive the AR of the activating ligands testosterone (T) and dihydrotestosterone (DHT) by limiting their biosynthesis or blocking AR binding. Notably, AR signaling is dichotomous, inducing growth at lower activity levels, while suppressing growth at higher levels. Recent clinical studies have exploited this effect by administration of supraphysiological concentrations of T, resulting in clinical responses and improvements in quality of life. However, the use of T as a therapeutic agent in oncology is limited by poor drug-like properties as well as rapid and variable metabolism. Here, we investigated the antitumor effects of selective AR modulators (SARMs), which are small-molecule nonsteroidal AR agonists developed to treat muscle wasting and cachexia. Several orally administered SARMs activated the AR program in PC models. AR cistromes regulated by steroidal androgens and SARMs were superimposable. Coregulatory proteins including HOXB13 and GRHL2 comprised AR complexes assembled by both androgens and SARMs. At bioavailable concentrations, SARMs repressed MYC oncoprotein expression and inhibited the growth of castration-sensitive and castration-resistant PC in vitro and in vivo. These results support further clinical investigation of SARMs for treating advanced PC.

Authors

Michael D. Nyquist, Lisa S. Ang, Alexandra Corella, Ilsa M. Coleman, Michael P. Meers, Anthony J. Christiani, Cordell Pierce, Derek H. Janssens, Hannah E. Meade, Arnab Bose, Lauren Brady, Timothy Howard, Navonil De Sarkar, Sander B. Frank, Ruth F. Dumpit, James T. Dalton, Eva Corey, Stephen R. Plymate, Michael C. Haffner, Elahe A. Mostaghel, Peter S. Nelson

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Figure 1

Selective AR modulators activate the canonical AR program in PC cells and repress tumor cell proliferation.

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Selective AR modulators activate the canonical AR program in PC cells an...
(A) Dose-response curves were determined in the LNCaP cell line for the steroidal androgens R1881 and T, the antiandrogen ENZ, and the nonsteroidal AR agonists T8039, GTX-024, GTX-027, and SARM-2F (n = 4). Data represent the mean ± SD. (B) Doses of R1881 and SARMs chosen for RNA-Seq analysis. Gene expression heatmaps are shown for the top 100 genes (C) induced or (D) repressed by treatment with 1 nM R1881 (n = 2). (E) Gene expression heatmap of genes that comprise the ARG.10 signature. (F) GSVA signature score heatmap for the AR-regulated gene sets ARG.10, AR_Induced, and AR_Repressed.