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Small Molecule Therapeutics

Combinatorial Efficacy of Olaparib with Radiation and ATR Inhibitor Requires PARP1 Protein in Homologous Recombination–Proficient Pancreatic Cancer

Leslie A. Parsels, Carl G. Engelke, Joshua Parsels, Sheryl A. Flanagan, Qiang Zhang, Daria Tanska, Daniel R. Wahl, Christine E. Canman, Theodore S. Lawrence and Meredith A. Morgan
Leslie A. Parsels
1Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, Michigan.
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Carl G. Engelke
1Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, Michigan.
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Joshua Parsels
1Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, Michigan.
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Sheryl A. Flanagan
1Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, Michigan.
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Qiang Zhang
1Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, Michigan.
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Daria Tanska
1Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, Michigan.
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Daniel R. Wahl
1Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, Michigan.
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Christine E. Canman
2Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan.
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Theodore S. Lawrence
1Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, Michigan.
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  • ORCID record for Theodore S. Lawrence
Meredith A. Morgan
1Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, Michigan.
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  • For correspondence: mmccrack@med.umich.edu
DOI: 10.1158/1535-7163.MCT-20-0365 Published February 2021
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Abstract

PARP inhibitor monotherapy (olaparib) was recently FDA approved for the treatment of BRCA1/2-mutant, homologous recombination (HR) repair-deficient pancreatic cancer. Most pancreatic cancers, however, are HR proficient and thus resistant to PARP inhibitor monotherapy. We tested the hypothesis that combined therapy with radiation and ataxia telangiectasia and Rad3-related (ATR) inhibitor (AZD6738) would extend the therapeutic indication of olaparib to HR-proficient pancreatic cancers. We show that olaparib combined with AZD6738 significantly reduced radiation survival relative to either agent alone, regardless of HR status. Whereas catalytic inhibition of PARP with low concentrations of olaparib radiosensitized HR-deficient models, maximal sensitization in HR-proficient models required concentrations of olaparib that induce formation of PARP1–DNA complexes. Furthermore, CRISPR-Cas9–mediated PARP1 deletion failed to recapitulate the effects of olaparib on radiosensitivity and negated the combinatorial efficacy of olaparib and AZD6738 on radiosensitization, suggesting that PARP1–DNA complexes, rather than PARP catalytic inhibition, were responsible for radiosensitization. Mechanistically, therapeutic concentrations of olaparib in combination with radiation and AZD6738 increased DNA double-strand breaks. DNA fiber combing revealed that high concentrations of olaparib did not stall replication forks but instead accelerated replication fork progression in association with an ATR-mediated replication stress response that was antagonized by AZD6738. Finally, in HR-proficient tumor xenografts, the combination of olaparib, radiation, and AZD6738 significantly delayed tumor growth compared with all other treatments. These findings suggest that PARP1–DNA complexes are required for the therapeutic activity of olaparib combined with radiation and ATR inhibitor in HR-proficient pancreatic cancer and support the clinical development of this combination for tumors intrinsically resistant to PARP inhibitors.

This article is featured in Highlights of This Issue, p. 217

Footnotes

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

  • Mol Cancer Ther 2021;20:263–73

  • Received May 4, 2020.
  • Revision received July 6, 2020.
  • Accepted November 9, 2020.
  • Published first December 2, 2020.
  • ©2020 American Association for Cancer Research.
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Molecular Cancer Therapeutics: 20 (2)
February 2021
Volume 20, Issue 2
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Combinatorial Efficacy of Olaparib with Radiation and ATR Inhibitor Requires PARP1 Protein in Homologous Recombination–Proficient Pancreatic Cancer
Leslie A. Parsels, Carl G. Engelke, Joshua Parsels, Sheryl A. Flanagan, Qiang Zhang, Daria Tanska, Daniel R. Wahl, Christine E. Canman, Theodore S. Lawrence and Meredith A. Morgan
Mol Cancer Ther February 1 2021 (20) (2) 263-273; DOI: 10.1158/1535-7163.MCT-20-0365

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Combinatorial Efficacy of Olaparib with Radiation and ATR Inhibitor Requires PARP1 Protein in Homologous Recombination–Proficient Pancreatic Cancer
Leslie A. Parsels, Carl G. Engelke, Joshua Parsels, Sheryl A. Flanagan, Qiang Zhang, Daria Tanska, Daniel R. Wahl, Christine E. Canman, Theodore S. Lawrence and Meredith A. Morgan
Mol Cancer Ther February 1 2021 (20) (2) 263-273; DOI: 10.1158/1535-7163.MCT-20-0365
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Molecular Cancer Therapeutics
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