Supraphysiological androgens suppress prostate cancer growth through androgen receptor-mediated DNA damage

Payel Chatterjee; Michael T. Schweizer; Jared M. Lucas; Ilsa Coleman; Michael D. Nyquist; Sander B. Frank; Robin Tharakan; Elahe Mostaghel; Jun Luo; Colin C. Pritchard; Hung Ming Lam; Eva Corey; Emmanuel S. Antonarakis; Samuel R. Denmeade; Peter S. Nelson

doi:10.1172/JCI127613

Supraphysiological androgens suppress prostate cancer growth through androgen receptor-mediated DNA damage

Payel Chatterjee, Michael T. Schweizer, Jared M. Lucas, Ilsa Coleman, Michael D. Nyquist, Sander B. Frank, Robin Tharakan, Elahe Mostaghel, Jun Luo, Colin C. Pritchard, Hung Ming Lam, Eva Corey, Emmanuel S. Antonarakis, Samuel R. Denmeade, Peter S. Nelson

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

60 Scopus citations

Abstract

Prostate cancer (PC) initially depends on androgen receptor (AR) signaling for survival and growth. Therapeutics designed to suppress AR activity serve as the primary intervention for advanced disease. However, supraphysiological androgen (SPA) concentrations can produce paradoxical responses leading to PC growth inhibition. We sought to discern the mechanisms by which SPA inhibits PC and to determine if molecular context associates with antitumor activity. SPA produced an ARmediated, dose-dependent induction of DNA double-strand breaks, G0/G1 cell-cycle arrest, and cellular senescence. SPA repressed genes involved in DNA repair and delayed the restoration of damaged DNA, which was augmented by poly (ADPribose) polymerase 1 inhibition. SPA-induced double-strand breaks were accentuated in BRCA2-deficient patients with PC, and combining SPA with poly (ADP-ribose) polymerase or DNA-dependent protein kinase inhibition further repressed growth. Next-generation sequencing was performed on biospecimens from patients with PC receiving SPA as part of ongoing phase II clinical trials. Patients with mutations in genes mediating homology-directed DNA repair were more likely to exhibit clinical responses to SPA. These results provide a mechanistic rationale for directing SPA therapy to patients with PC who have AR amplification or DNA repair deficiency and for combining SPA therapy with poly (ADP-ribose) polymerase inhibition.

Original language	English (US)
Pages (from-to)	4245-4260
Number of pages	16
Journal	Journal of Clinical Investigation
Volume	129
Issue number	10
DOIs	https://doi.org/10.1172/JCI127613
State	Published - Oct 1 2019
Externally published	Yes

Bibliographical note

Funding Information:
We are grateful to the patients who participated in these studies. We acknowledge the Fred Hutch Scientific Imaging Shared Resource for assistance with imaging experiments. We thank Holly Nguyen, Lisha Brown, and Lisa Ang for their technical support involving LuCaP tumor studies. We gratefully acknowledge research support from Fred Hutch/University of Washington Cancer Consortium grant P30CA015704-40, NIH P50CA97186, R21CA194798, P01CA163227, and Congressionally Directed Medical Research Program (CDMRP) Awards PC170503 and PC170431. PC was supported by a CDMRP postdoctoral fellowship award W81XWH-15-1-0535. MDN was supported by a CDMRP postdoctoral fellowship award W81XWH-16-1-0206. MTS was supported by a Prostate Cancer Foundation Young Investigator Award and a Department of Defense (DOD) award W81XWH-16-1-0484. JL is supported by National Cancer Institute CA185297 and a DOD CDMRP award W81XWH-15-2-0050. ESA is partially supported by NIH grants P30CA006973 and R01 CA185297 and CDMRP grant W81XWH-16-PCRP-CCRSA. CCP was supported by DOD awards PC170510, PC170503P2, and PC141019.

Publisher Copyright:
© 2019, American Society for Clinical Investigation.

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Chatterjee, P., Schweizer, M. T., Lucas, J. M., Coleman, I., Nyquist, M. D., Frank, S. B., Tharakan, R., Mostaghel, E., Luo, J., Pritchard, C. C., Lam, H. M., Corey, E., Antonarakis, E. S., Denmeade, S. R., & Nelson, P. S. (2019). Supraphysiological androgens suppress prostate cancer growth through androgen receptor-mediated DNA damage. Journal of Clinical Investigation, 129(10), 4245-4260. https://doi.org/10.1172/JCI127613

Chatterjee, P, Schweizer, MT, Lucas, JM, Coleman, I, Nyquist, MD, Frank, SB, Tharakan, R, Mostaghel, E, Luo, J, Pritchard, CC, Lam, HM, Corey, E, Antonarakis, ES, Denmeade, SR & Nelson, PS 2019, 'Supraphysiological androgens suppress prostate cancer growth through androgen receptor-mediated DNA damage', Journal of Clinical Investigation, vol. 129, no. 10, pp. 4245-4260. https://doi.org/10.1172/JCI127613

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title = "Supraphysiological androgens suppress prostate cancer growth through androgen receptor-mediated DNA damage",

abstract = "Prostate cancer (PC) initially depends on androgen receptor (AR) signaling for survival and growth. Therapeutics designed to suppress AR activity serve as the primary intervention for advanced disease. However, supraphysiological androgen (SPA) concentrations can produce paradoxical responses leading to PC growth inhibition. We sought to discern the mechanisms by which SPA inhibits PC and to determine if molecular context associates with antitumor activity. SPA produced an ARmediated, dose-dependent induction of DNA double-strand breaks, G0/G1 cell-cycle arrest, and cellular senescence. SPA repressed genes involved in DNA repair and delayed the restoration of damaged DNA, which was augmented by poly (ADPribose) polymerase 1 inhibition. SPA-induced double-strand breaks were accentuated in BRCA2-deficient patients with PC, and combining SPA with poly (ADP-ribose) polymerase or DNA-dependent protein kinase inhibition further repressed growth. Next-generation sequencing was performed on biospecimens from patients with PC receiving SPA as part of ongoing phase II clinical trials. Patients with mutations in genes mediating homology-directed DNA repair were more likely to exhibit clinical responses to SPA. These results provide a mechanistic rationale for directing SPA therapy to patients with PC who have AR amplification or DNA repair deficiency and for combining SPA therapy with poly (ADP-ribose) polymerase inhibition.",

author = "Payel Chatterjee and Schweizer, {Michael T.} and Lucas, {Jared M.} and Ilsa Coleman and Nyquist, {Michael D.} and Frank, {Sander B.} and Robin Tharakan and Elahe Mostaghel and Jun Luo and Pritchard, {Colin C.} and Lam, {Hung Ming} and Eva Corey and Antonarakis, {Emmanuel S.} and Denmeade, {Samuel R.} and Nelson, {Peter S.}",

note = "Funding Information: We are grateful to the patients who participated in these studies. We acknowledge the Fred Hutch Scientific Imaging Shared Resource for assistance with imaging experiments. We thank Holly Nguyen, Lisha Brown, and Lisa Ang for their technical support involving LuCaP tumor studies. We gratefully acknowledge research support from Fred Hutch/University of Washington Cancer Consortium grant P30CA015704-40, NIH P50CA97186, R21CA194798, P01CA163227, and Congressionally Directed Medical Research Program (CDMRP) Awards PC170503 and PC170431. PC was supported by a CDMRP postdoctoral fellowship award W81XWH-15-1-0535. MDN was supported by a CDMRP postdoctoral fellowship award W81XWH-16-1-0206. MTS was supported by a Prostate Cancer Foundation Young Investigator Award and a Department of Defense (DOD) award W81XWH-16-1-0484. JL is supported by National Cancer Institute CA185297 and a DOD CDMRP award W81XWH-15-2-0050. ESA is partially supported by NIH grants P30CA006973 and R01 CA185297 and CDMRP grant W81XWH-16-PCRP-CCRSA. CCP was supported by DOD awards PC170510, PC170503P2, and PC141019. Publisher Copyright: {\textcopyright} 2019, American Society for Clinical Investigation.",

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doi = "10.1172/JCI127613",

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AU - Chatterjee, Payel

AU - Schweizer, Michael T.

AU - Lucas, Jared M.

AU - Coleman, Ilsa

AU - Nyquist, Michael D.

AU - Frank, Sander B.

AU - Tharakan, Robin

AU - Mostaghel, Elahe

AU - Luo, Jun

AU - Pritchard, Colin C.

AU - Lam, Hung Ming

AU - Corey, Eva

AU - Antonarakis, Emmanuel S.

AU - Denmeade, Samuel R.

AU - Nelson, Peter S.

N1 - Funding Information: We are grateful to the patients who participated in these studies. We acknowledge the Fred Hutch Scientific Imaging Shared Resource for assistance with imaging experiments. We thank Holly Nguyen, Lisha Brown, and Lisa Ang for their technical support involving LuCaP tumor studies. We gratefully acknowledge research support from Fred Hutch/University of Washington Cancer Consortium grant P30CA015704-40, NIH P50CA97186, R21CA194798, P01CA163227, and Congressionally Directed Medical Research Program (CDMRP) Awards PC170503 and PC170431. PC was supported by a CDMRP postdoctoral fellowship award W81XWH-15-1-0535. MDN was supported by a CDMRP postdoctoral fellowship award W81XWH-16-1-0206. MTS was supported by a Prostate Cancer Foundation Young Investigator Award and a Department of Defense (DOD) award W81XWH-16-1-0484. JL is supported by National Cancer Institute CA185297 and a DOD CDMRP award W81XWH-15-2-0050. ESA is partially supported by NIH grants P30CA006973 and R01 CA185297 and CDMRP grant W81XWH-16-PCRP-CCRSA. CCP was supported by DOD awards PC170510, PC170503P2, and PC141019. Publisher Copyright: © 2019, American Society for Clinical Investigation.

PY - 2019/10/1

Y1 - 2019/10/1

N2 - Prostate cancer (PC) initially depends on androgen receptor (AR) signaling for survival and growth. Therapeutics designed to suppress AR activity serve as the primary intervention for advanced disease. However, supraphysiological androgen (SPA) concentrations can produce paradoxical responses leading to PC growth inhibition. We sought to discern the mechanisms by which SPA inhibits PC and to determine if molecular context associates with antitumor activity. SPA produced an ARmediated, dose-dependent induction of DNA double-strand breaks, G0/G1 cell-cycle arrest, and cellular senescence. SPA repressed genes involved in DNA repair and delayed the restoration of damaged DNA, which was augmented by poly (ADPribose) polymerase 1 inhibition. SPA-induced double-strand breaks were accentuated in BRCA2-deficient patients with PC, and combining SPA with poly (ADP-ribose) polymerase or DNA-dependent protein kinase inhibition further repressed growth. Next-generation sequencing was performed on biospecimens from patients with PC receiving SPA as part of ongoing phase II clinical trials. Patients with mutations in genes mediating homology-directed DNA repair were more likely to exhibit clinical responses to SPA. These results provide a mechanistic rationale for directing SPA therapy to patients with PC who have AR amplification or DNA repair deficiency and for combining SPA therapy with poly (ADP-ribose) polymerase inhibition.

AB - Prostate cancer (PC) initially depends on androgen receptor (AR) signaling for survival and growth. Therapeutics designed to suppress AR activity serve as the primary intervention for advanced disease. However, supraphysiological androgen (SPA) concentrations can produce paradoxical responses leading to PC growth inhibition. We sought to discern the mechanisms by which SPA inhibits PC and to determine if molecular context associates with antitumor activity. SPA produced an ARmediated, dose-dependent induction of DNA double-strand breaks, G0/G1 cell-cycle arrest, and cellular senescence. SPA repressed genes involved in DNA repair and delayed the restoration of damaged DNA, which was augmented by poly (ADPribose) polymerase 1 inhibition. SPA-induced double-strand breaks were accentuated in BRCA2-deficient patients with PC, and combining SPA with poly (ADP-ribose) polymerase or DNA-dependent protein kinase inhibition further repressed growth. Next-generation sequencing was performed on biospecimens from patients with PC receiving SPA as part of ongoing phase II clinical trials. Patients with mutations in genes mediating homology-directed DNA repair were more likely to exhibit clinical responses to SPA. These results provide a mechanistic rationale for directing SPA therapy to patients with PC who have AR amplification or DNA repair deficiency and for combining SPA therapy with poly (ADP-ribose) polymerase inhibition.

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Supraphysiological androgens suppress prostate cancer growth through androgen receptor-mediated DNA damage

Abstract

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