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 8

AR signature scores identify potential responders in clinical castration-resistant prostate cancer samples.

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AR signature scores identify potential responders in clinical castration...
(A) Heatmaps of gene set variation analysis (GSVA) signature scores comparing previously published gene signatures with gene signatures derived in the current study. (B) Correlation of biphasic and AR-induced signature scores in n = 212 CRPC tumor specimens, colored by neuroendocrine (NE.10) signature score values. Quadrants Q1–Q4 are delineated by hatched lines. Signature scores are indicated for vehicle-treated (veh) or high-dose testosterone–treated (HiT) responder (R) or nonresponder (NR) PDX lines for (C) biphasic, (D) inverse-biphasic, (E) AR-induced, and (F) AR-repressed gene sets. (G) Diagram of an interactive web of factors that mediate sensitivity (red) and resistance (green) to AR-directed therapies. (H) The relationship between AR signaling and prostate cancer throughout disease progression is diagrammed.