Response to supraphysiological testosterone is predicted by a distinct androgen receptor cistrome.

The androgen receptor (AR) is a master transcription factor that regulates prostate cancer (PC) development and progression. Inhibition of AR signaling by androgen deprivation is the first-line therapy with initial efficacy for advanced and recurrent PC. Paradoxically, supraphysiological levels of testosterone (SPT) also inhibit PC progression. However, as with any therapy, not all patients show a therapeutic benefit, and responses differ widely in magnitude and duration. In this study, we evaluated whether differences in the AR cistrome before treatment can distinguish between SPT-responding (R) and -nonresponding (NR) tumors. We provide the first preclinical evidence to our knowledge that SPT-R tumors exhibit a distinct AR cistrome when compared with SPT-NR tumors, indicating a differential biological role of the AR. We applied an integrated analysis of ChIP-Seq and RNA-Seq to the pretreatment tumors and identified an SPT-R signature that distinguishes R and NR tumors. Because transcriptomes of SPT-treated clinical specimens are not available, we interrogated available castration-resistant PC (CRPC) transcriptomes and showed that the SPT-R signature is associated with improved survival and has the potential to identify patients who would respond to SPT. These findings provide an opportunity to identify the subset of patients with CRPC who would benefit from SPT therapy.

JCI insight. 2022 May 23*** epublish ***

Xintao Qiu, Lisha G Brown, Jennifer L Conner, Holly M Nguyen, Nadia Boufaied, Sarah Abou Alaiwi, Ji-Heui Seo, Talal El Zarif, Connor Bell, Edward O'Connor, Brian Hanratty, Mark Pomerantz, Matthew L Freedman, Myles Brown, Michael C Haffner, Peter S Nelson, Felix Y Feng, David P Labbé, Henry W Long, Eva Corey

Center for Functional Cancer Epigenetics, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA., Department of Urology, University of Washington, Seattle, Washington, USA., Cancer Research Program, Research Institute of the McGill University Health Centre, Montréal, Québec, Canada., Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA., University of California at San Francisco, San Francisco, California, USA.

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