Molecular determinants of response to high-dose androgen therapy in prostate cancer
Michael D. Nyquist, … , Peter S. Nelson, Elahe A. Mostaghel
Michael D. Nyquist, … , Peter S. Nelson, Elahe A. Mostaghel
Published September 10, 2019
Citation Information: JCI Insight. 2019;4(19):e129715. https://doi.org/10.1172/jci.insight.129715.
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Research Article Genetics Oncology

Molecular determinants of response to high-dose androgen therapy in prostate cancer

Abstract

Clinical trials of high-dose androgen (HDA) therapy for prostate cancer (PC) have shown promising efficacy but are limited by lack of criteria to identify likely responders. To elucidate factors that govern the growth-repressive effects of HDAs, we applied an unbiased integrative approach using genetic screens and transcriptional profiling of PC cells with or without demonstrated phenotypic sensitivity to androgen-mediated growth repression. Through this comprehensive analysis, we identified genetic events and related signaling networks that determine the response to both HDA and androgen withdrawal. We applied these findings to develop a gene signature that may serve as an early indicator of treatment response and identify men with tumors that are amenable to HDA therapy.

Authors

Michael D. Nyquist, Alexandra Corella, Osama Mohamad, Ilsa Coleman, Arja Kaipainen, Daniel A. Kuppers, Jared M. Lucas, Patrick J. Paddison, Stephen R. Plymate, Peter S. Nelson, Elahe A. Mostaghel

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Figure 6

Suppression of biphasic gene expression is an innate function of AR.

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Suppression of biphasic gene expression is an innate function of AR. (A)...
(A) Heatmaps of custom gene expression signature scores (top) and RNA-seq mean-centered log2(CPM) values (bottom) for the hTERT-immortalized prostate epithelial cell line 957E/hTERT that was engineered to overexpress AR. Cells were treated with either 1 nM R1881 or ethanol. Examples were selected from the top 250 upregulated or downregulated genes. (B) Percentage of genes in each AR gene signature associated with at least 1 ChIP-seq peak for AR, RB1, or E2F1 subtracted by the percentage of genes bound by at least 1 peak in the whole genome. ChIP-seq data sets for both LNCaP and VCAP were compared. (C) Graph of DNA-damage-response (DDR) and cell-cycle (CC) genes previously shown to be bound by AR and are regulated by AR activity. Blue squares indicate the presence of a gene in an AR gene signature for 3 out of 4 HDA-sensitive cell lines. Black bars represent the study that validated the gene as regulated (UP) or downregulated (DN) by androgens.