Expression of the androgen receptor governs radiation resistance in a subset of glioblastomas vulnerable to antiandrogen therapy

Christian K. Werner, Uchechi J. Nna, Hanshi Sun, Kari Wilder-Romans, Joseph Dresser, Ayesha U. Kothari, Weihua Zhou, Yangyang Yao, Arvind Rao, Stefanie Stallard, Carl Koschmann, Tarik Bor, Waldemar Debinski, Alexander M. Hegedus, Meredith A. Morgan, Sriram Venneti, Edwina Baskin-Bey, Daniel E. Spratt, Howard Colman, Jann N. SarkariaArul M. Chinnaiyan, Joel R. Eisner, Corey Speers, Theodore S. Lawrence, Roy E. Strowd, Daniel R. Wahl

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

New approaches are needed to overcome intrinsic therapy resistance in glioblastoma (GBM). Because GBMs exhibit sexual dimorphism and are reported to express steroid hormone receptors, we reasoned that signaling through the androgen receptor (AR) could mediate therapy resistance in GBM, much as it does in AR-positive prostate and breast cancers. We found that nearly half of GBM cell lines, patient-derived xenografts (PDX), and human tumors expressed AR at the transcript and protein level—with expression levels overlapping those of primary prostate cancer. Analysis of gene expression datasets also revealed that AR expression is higher in GBM patient samples than normal brain tissue. Multiple clinical-grade antiandrogens slowed the growth of and radiosensitized AR-positive GBM cell lines and PDXs in vitro and in vivo. Antiandrogens blocked the ability of AR-positive GBM PDXs to engage adaptive transcriptional programs following radiation and slowed the repair of radiation-induced DNA damage. These results suggest that combining blood–brain barrier permeable antiandrogens with radiation may have promise for patients with AR-positive GBMs.

Original languageEnglish (US)
Pages (from-to)2163-2174
Number of pages12
JournalMolecular cancer therapeutics
Volume19
Issue number10
DOIs
StatePublished - Oct 1 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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