Androgen receptor upregulation mediates radioresistance after ionizing radiation

Daniel E. Spratt, Michael J. Evans, Brian J. Davis, Michael G. Doran, Man Xia Lee, Neel Shah, John Wongvipat, Kathryn E. Carnazza, George G. Klee, William Polkinghorn, Donald J. Tindall, Jason S. Lewis, Charles L. Sawyers

Research output: Contribution to journalArticlepeer-review

68 Scopus citations

Abstract

Clinical trials have established the benefit of androgen deprivation therapy (ADT) combined with radiotherapy in prostate cancer. ADT sensitizes prostate cancer to radiotherapy-induced death at least in part through inhibition of DNA repair machinery, but for unknown reasons, adjuvant ADT provides further survival benefits. Here, we show that androgen receptor (AR) expression and activity are durably upregulated following radiotherapy in multiple human prostate cancer models in vitro and in vivo. Moreover, the degree of AR upregulation correlates with survival in vitro and time to tumor progression in animal models. We also provide evidence of AR pathway upregulation, measured by a rise in serum levels of AR-regulated hK2 protein, in nearly 20% of patients after radiotherapy. Furthermore, these men were three-fold more likely to experience subsequent biochemical failure. Collectively, these data demonstrate that radiotherapy can upregulate AR signaling after therapy to an extent that negatively affects disease progression and/or survival.

Original languageEnglish (US)
Pages (from-to)4688-4696
Number of pages9
JournalCancer research
Volume75
Issue number22
DOIs
StatePublished - Nov 15 2015

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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