Molecular determinants of response to high-dose androgen therapy in prostate cancer
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
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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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 7

De novo resistance to high-dose androgen is associated with loss of differentiation and gain of a mitotic gene expression profile.

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De novo resistance to high-dose androgen is associated with loss of diff...
(A) Gene set enrichment analysis (GSEA) plots of normalized-enrichment scores (NES) and FDR values for differentially expressed genes between R1AD1 and the 4 HDA-sensitive cell lines when treated with 10 nM R1881 (FDR < 0.05). (B) Heatmap of RNA-seq Log2(CPM) values, mean-centered across all cell lines, of a selection of the 250 most upregulated genes in R1AD1 cells treated compared with LNCaP, VCAP, LAPC4, and 22PC-EP when treated with 10 nM R1881 (bottom). Black squares indicate positive status as a biphasic gene or Hallmark_E2F_target gene. Log2(fold change) in gene expression from vehicle control when treated with 10 nM R1881 for (C) FOXM1 and (D) CCNA2. (E) Heatmaps of RNA-seq mean-centered Log2(CPM) values of a subset of the 250 most downregulated genes in R1AD1 compared with LNCaP, VCAP, LAPC4, and 22PC-EP when treated with 10 nM R1881 (bottom). Black squares indicate positive status as an AR-induced, Hallmark_Androgen_Response, or AR-coregulator gene. (F) Log2(fold change) in MYC expression from vehicle control when treated with 10 nM R1881.