Androgen Receptor Variants Mediate DNA Repair after Prostate Cancer Irradiation.

Abstract

In prostate cancer, androgen deprivation therapy (ADT) enhances the cytotoxic effects of radiotherapy. This effect is associated with weakening of the DNA damage response (DDR) normally supported by the androgen receptor. As a significant number of patients will fail combined ADT and radiotherapy, we hypothesized that DDR may be driven by androgen receptor splice variants (ARV) induced by ADT. Investigating this hypothesis, we found that ARVs increase the clonogenic survival of prostate cancer cells after irradiation in an ADT-independent manner. Notably, prostate cancer cell irradiation triggers binding of ARV to the catalytic subunit of the critical DNA repair kinase DNA-PK. Pharmacologic inhibition of DNA-PKc blocked this interaction, increased DNA damage, and elevated prostate cancer cell death after irradiation. Our findings provide a mechanistic rationale for therapeutic targeting of DNA-PK in the context of combined ADT and radiotherapy as a strategy to radiosensitize clinically localized prostate cancer. Cancer Res; 77(18); 4745-54. ©2017 AACR.

• Authors: Yi Yin, Rui Li, Kangling Xu, Sentai Ding, Jeffrey Li, GuemHee Baek, Susmita G Ramanand, Sam Ding, Zhao Liu, Yunpeng Gao, Mohammed S Kanchwala, Xiangyi Li, Ryan Hutchinson, Xihui Liu, Solomon L Woldu, Chao Xing, Neil B Desai, Felix Y Feng, Sandeep Burma, Johann S de Bono, Scott M Dehm, Ram S Mani, Benjamin P C Chen, Ganesh V Raj
• Journal: Cancer research (Cancer Res) Vol. 77 Issue 18 Pg. 4745-4754 (09 15 2017) ISSN: 1538-7445 [Electronic] United States
• PMID: 28754673 (Publication Type: Journal Article)
• Copyright: ©2017 American Association for Cancer Research.

Chemical References

• AR protein, human
• Androgen Antagonists
• Antineoplastic Agents
• Benzamides
• Nitriles
• Protein Kinase Inhibitors
• Receptors, Androgen
• Phenylthiohydantoin
• enzalutamide
• DNA-Activated Protein Kinase

Topics

• Androgen Antagonists (pharmacology)
• Animals
• Antineoplastic Agents (pharmacology)
• Benzamides
• DNA Repair (genetics, radiation effects)
• DNA-Activated Protein Kinase (antagonists & inhibitors, metabolism)
• Humans
• Male
• Mice
• Mice, Nude
• Nitriles
• Phenylthiohydantoin (analogs & derivatives, pharmacology)
• Prostatic Neoplasms (drug therapy, genetics, radiotherapy)
• Protein Kinase Inhibitors (pharmacology)
• Radiation, Ionizing
• Receptors, Androgen (chemistry, genetics, metabolism)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays