Androgen Receptor Variants Mediate DNA Repair after Prostate Cancer Irradiation.
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Date
2017-09-15ICR Author
Author
Yin, Y
Li, R
Xu, K
Ding, S
Li, J
Baek, G
Ramanand, SG
Ding, S
Liu, Z
Gao, Y
Kanchwala, MS
Li, X
Hutchinson, R
Liu, X
Woldu, SL
Xing, C
Desai, NB
Feng, FY
Burma, S
de Bono, JS
Dehm, SM
Mani, RS
Chen, BPC
Raj, GV
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
Tumor Cells, Cultured
Animals
Humans
Mice
Mice, Nude
Prostatic Neoplasms
Phenylthiohydantoin
Androgen Antagonists
Receptors, Androgen
Antineoplastic Agents
Protein Kinase Inhibitors
Xenograft Model Antitumor Assays
DNA Repair
Radiation, Ionizing
Male
DNA-Activated Protein Kinase
Research team
Prostate Cancer Targeted Therapy Group
Language
eng
Date accepted
2017-07-20
License start date
2017-09
Citation
Cancer research, 2017, 77 (18), pp. 4745 - 4754
Publisher
AMER ASSOC CANCER RESEARCH