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Cell Death and Survival

PARP1 Trapping by PARP Inhibitors Drives Cytotoxicity in Both Cancer Cells and Healthy Bone Marrow

Todd A. Hopkins, William B. Ainsworth, Paul A. Ellis, Cherrie K. Donawho, Enrico L. DiGiammarino, Sanjay C. Panchal, Vivek C. Abraham, Mikkel A. Algire, Yan Shi, Amanda M. Olson, Eric F. Johnson, Julie L. Wilsbacher and David Maag
Todd A. Hopkins
AbbVie, Inc., North Chicago, Illinois.
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William B. Ainsworth
AbbVie, Inc., North Chicago, Illinois.
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Paul A. Ellis
AbbVie, Inc., North Chicago, Illinois.
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Cherrie K. Donawho
AbbVie, Inc., North Chicago, Illinois.
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Enrico L. DiGiammarino
AbbVie, Inc., North Chicago, Illinois.
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Sanjay C. Panchal
AbbVie, Inc., North Chicago, Illinois.
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Vivek C. Abraham
AbbVie, Inc., North Chicago, Illinois.
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Mikkel A. Algire
AbbVie, Inc., North Chicago, Illinois.
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Yan Shi
AbbVie, Inc., North Chicago, Illinois.
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Amanda M. Olson
AbbVie, Inc., North Chicago, Illinois.
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Eric F. Johnson
AbbVie, Inc., North Chicago, Illinois.
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Julie L. Wilsbacher
AbbVie, Inc., North Chicago, Illinois.
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David Maag
AbbVie, Inc., North Chicago, Illinois.
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  • For correspondence: David.Maag@abbvie.com
DOI: 10.1158/1541-7786.MCR-18-0138
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Abstract

PARP inhibitors have recently been approved as monotherapies for the treatment of recurrent ovarian cancer and metastatic BRCA-associated breast cancer, and ongoing studies are exploring additional indications and combinations with other agents. PARP inhibitors trap PARP onto damaged chromatin when combined with temozolomide and methyl methanesulfonate, but the clinical relevance of these findings remains unknown. PARP trapping has thus far been undetectable in cancer cells treated with PARP inhibitors alone. Here, we evaluate the contribution of PARP trapping to the tolerability and efficacy of PARP inhibitors in the monotherapy setting. We developed a novel implementation of the proximity ligation assay to detect chromatin-trapped PARP1 at single-cell resolution with higher sensitivity and throughput than previously reported methods. We further demonstrate that the PARP inhibitor–induced trapping appears to drive single-agent cytotoxicity in healthy human bone marrow, indicating that the toxicity of trapped PARP complexes is not restricted to cancer cells with homologous recombination deficiency. Finally, we show that PARP inhibitors with dramatically different trapping potencies exhibit comparable tumor growth inhibition at MTDs in a xenograft model of BRCA1-mutant triple-negative breast cancer. These results are consistent with emerging clinical data and suggest that the inverse relationship between trapping potency and tolerability may limit the potential therapeutic advantage of potent trapping activity.

Implications: PARP trapping contributes to single-agent cytotoxicity of PARP inhibitors in both cancer cells and healthy bone marrow, and the therapeutic advantage of potent trapping activity appears to be limited.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/).

  • Received February 14, 2018.
  • Revision received August 31, 2018.
  • Accepted October 23, 2018.
  • Published first November 14, 2018.
  • ©2018 American Association for Cancer Research.
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This OnlineFirst version was published on January 11, 2019
doi: 10.1158/1541-7786.MCR-18-0138

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PARP1 Trapping by PARP Inhibitors Drives Cytotoxicity in Both Cancer Cells and Healthy Bone Marrow
Todd A. Hopkins, William B. Ainsworth, Paul A. Ellis, Cherrie K. Donawho, Enrico L. DiGiammarino, Sanjay C. Panchal, Vivek C. Abraham, Mikkel A. Algire, Yan Shi, Amanda M. Olson, Eric F. Johnson, Julie L. Wilsbacher and David Maag
Mol Cancer Res January 11 2019 DOI: 10.1158/1541-7786.MCR-18-0138

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PARP1 Trapping by PARP Inhibitors Drives Cytotoxicity in Both Cancer Cells and Healthy Bone Marrow
Todd A. Hopkins, William B. Ainsworth, Paul A. Ellis, Cherrie K. Donawho, Enrico L. DiGiammarino, Sanjay C. Panchal, Vivek C. Abraham, Mikkel A. Algire, Yan Shi, Amanda M. Olson, Eric F. Johnson, Julie L. Wilsbacher and David Maag
Mol Cancer Res January 11 2019 DOI: 10.1158/1541-7786.MCR-18-0138
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