Androgen receptor variants mediate DNA repair after prostate cancer irradiation

Yi Yin; Rui Li; Kangling Xu; Sentai Ding; Jeffrey Li; Guem Hee 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

doi:10.1158/0008-5472.CAN-17-0164

Androgen receptor variants mediate DNA repair after prostate cancer irradiation

Yi Yin, Rui Li, Kangling Xu, Sentai Ding, Jeffrey Li, Guem Hee 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 BonoScott M. Dehm, Ram S. Mani, Benjamin P.C. Chen, Ganesh V. Raj

Laboratory Medicine and Pathology

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English (US)
Pages (from-to)	4745-4754
Number of pages	10
Journal	Cancer Research
Volume	77
Issue number	18
DOIs	https://doi.org/10.1158/0008-5472.CAN-17-0164
State	Published - Sep 15 2017

Bibliographical note

Funding Information:
This work was supported by the following grants: W81XWH-15-1-0128 (to Y. Yin), W81XWH-14-1-0556 (to Y.Yin), W81XWH-13-2-0093 (to G.V. Raj), and W81XWH-12-1-0288 (to G. V. Raj) from the Department of Defense, 1R01CA200787-01 (to G.V. Raj), R01CA174777 (to S.M. Dehm), RO1CA149461, RO1CA197796 and R21CA202403 (to S. Burma), R01CA166677 (to B.P. Chen), UL1TR001105 (to C. Xing), and R00CA160640 (to R. S. Mani) from the NIH, NNX16AD78G from the National Aeronautics and Space Administration (to S. Burma), and the Mimi and John Cole Prostate Cancer Fund (to G.V. Raj).

Funding Information:
F.Y. Feng is the founder of PFS Genomics, reports receiving a commercial research grant from Varian, and is a consultant/advisory board member for Dendreon, EMD Serono, Ferring, Janssen, Medivation/Astellas, and Sanofi. J.S. de Bono has received speakers bureau honoraria from AstraZeneca and is a consultant/advisory board member for Astellas, AstraZeneca, Bayer, Genentech/

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©2017 AACR.

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10.1158/0008-5472.CAN-17-0164

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5600864

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Yin, Y., Li, R., Xu, K., Ding, S., Li, J., Baek, G. H., Ramanand, S. G., Ding, S., Liu, Z., Gao, Y., Kanchwala, M. S., Li, X., Hutchinson, R., Liu, X., Woldu, S. L., Xing, C., Desai, N. B., Feng, F. Y., Burma, S., ... Raj, G. V. (2017). Androgen receptor variants mediate DNA repair after prostate cancer irradiation. Cancer Research, 77(18), 4745-4754. https://doi.org/10.1158/0008-5472.CAN-17-0164

Yin, Y, Li, R, Xu, K, Ding, S, Li, J, Baek, GH, 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 2017, 'Androgen receptor variants mediate DNA repair after prostate cancer irradiation', Cancer Research, vol. 77, no. 18, pp. 4745-4754. https://doi.org/10.1158/0008-5472.CAN-17-0164

@article{aa9a24d7f00a4939ab7c6bee75c478ec,

title = "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.",

author = "Yi Yin and Rui Li and Kangling Xu and Sentai Ding and Jeffrey Li and Baek, {Guem Hee} and Ramanand, {Susmita G.} and Sam Ding and Zhao Liu and Yunpeng Gao and Kanchwala, {Mohammed S.} and Xiangyi Li and Ryan Hutchinson and Xihui Liu and Woldu, {Solomon L.} and Chao Xing and Desai, {Neil B.} and Feng, {Felix Y.} and Sandeep Burma and {De Bono}, {Johann S.} and Dehm, {Scott M.} and Mani, {Ram S.} and Chen, {Benjamin P.C.} and Raj, {Ganesh V.}",

note = "Funding Information: This work was supported by the following grants: W81XWH-15-1-0128 (to Y. Yin), W81XWH-14-1-0556 (to Y.Yin), W81XWH-13-2-0093 (to G.V. Raj), and W81XWH-12-1-0288 (to G. V. Raj) from the Department of Defense, 1R01CA200787-01 (to G.V. Raj), R01CA174777 (to S.M. Dehm), RO1CA149461, RO1CA197796 and R21CA202403 (to S. Burma), R01CA166677 (to B.P. Chen), UL1TR001105 (to C. Xing), and R00CA160640 (to R. S. Mani) from the NIH, NNX16AD78G from the National Aeronautics and Space Administration (to S. Burma), and the Mimi and John Cole Prostate Cancer Fund (to G.V. Raj). Funding Information: F.Y. Feng is the founder of PFS Genomics, reports receiving a commercial research grant from Varian, and is a consultant/advisory board member for Dendreon, EMD Serono, Ferring, Janssen, Medivation/Astellas, and Sanofi. J.S. de Bono has received speakers bureau honoraria from AstraZeneca and is a consultant/advisory board member for Astellas, AstraZeneca, Bayer, Genentech/ Publisher Copyright: {\textcopyright}2017 AACR.",

year = "2017",

month = sep,

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doi = "10.1158/0008-5472.CAN-17-0164",

language = "English (US)",

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T1 - Androgen receptor variants mediate DNA repair after prostate cancer irradiation

AU - Yin, Yi

AU - Li, Rui

AU - Xu, Kangling

AU - Ding, Sentai

AU - Li, Jeffrey

AU - Baek, Guem Hee

AU - Ramanand, Susmita G.

AU - Ding, Sam

AU - Liu, Zhao

AU - Gao, Yunpeng

AU - Kanchwala, Mohammed S.

AU - Li, Xiangyi

AU - Hutchinson, Ryan

AU - Liu, Xihui

AU - Woldu, Solomon L.

AU - Xing, Chao

AU - Desai, Neil B.

AU - Feng, Felix Y.

AU - Burma, Sandeep

AU - De Bono, Johann S.

AU - Dehm, Scott M.

AU - Mani, Ram S.

AU - Chen, Benjamin P.C.

AU - Raj, Ganesh V.

N1 - Funding Information: This work was supported by the following grants: W81XWH-15-1-0128 (to Y. Yin), W81XWH-14-1-0556 (to Y.Yin), W81XWH-13-2-0093 (to G.V. Raj), and W81XWH-12-1-0288 (to G. V. Raj) from the Department of Defense, 1R01CA200787-01 (to G.V. Raj), R01CA174777 (to S.M. Dehm), RO1CA149461, RO1CA197796 and R21CA202403 (to S. Burma), R01CA166677 (to B.P. Chen), UL1TR001105 (to C. Xing), and R00CA160640 (to R. S. Mani) from the NIH, NNX16AD78G from the National Aeronautics and Space Administration (to S. Burma), and the Mimi and John Cole Prostate Cancer Fund (to G.V. Raj). Funding Information: F.Y. Feng is the founder of PFS Genomics, reports receiving a commercial research grant from Varian, and is a consultant/advisory board member for Dendreon, EMD Serono, Ferring, Janssen, Medivation/Astellas, and Sanofi. J.S. de Bono has received speakers bureau honoraria from AstraZeneca and is a consultant/advisory board member for Astellas, AstraZeneca, Bayer, Genentech/ Publisher Copyright: ©2017 AACR.

PY - 2017/9/15

Y1 - 2017/9/15

N2 - 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.

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ER -

Androgen receptor variants mediate DNA repair after prostate cancer irradiation

Abstract

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