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Molecular Cancer Research
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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 Published February 2019
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    Figure 1.

    Biochemical and cellular characterization of talazoparib, A-934935, and rucaparib. A, Talazoparib, A-934935, and rucaparib have similar PARP1-binding properties as determined by surface plasmon resonance. B, Inhibition of PAR synthesis in HeyA8 cells by the compounds. C, Analysis of talazoparib, rucaparib, and 934935 trapping of PARP1 onto single-strand breaks in a biochemical system. D, Trapping of PARP1 onto chromatin after treatment of HeyA8 cells with combinations of 1 mmol/L MMS plus talazoparib, rucaparib, or A-934935. E, Potentiation of MMS-induced DNA damage measured by γH2A.X staining after treatment of HeyA8 cells with talazoparib, rucaparib, or A-934935. Data in B–E are presented as mean ± SEM from at least three independent experiments.

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    Figure 2.

    Cytotoxicity of talazoparib is driven by PARP1. Cell viability dose–response curves for talazoparib, A-934935, and rucaparib following treatment of HAP1 wt and HAP1 PARP1 knockout cells for 5 days. Data points are mean ± SEM from three independent experiments.

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    Figure 3.

    PARP1 trapping induced by veliparib can be detected by PLA in BRCA1 and BRCA2 synthetic lethal cell line models. Dose-dependent inhibition of auto-PARylation (black line) and dose-dependent increased activation of apoptosis marker caspase 3/7 (blue), DNA damage marker γH2A.X (orange), and PLA (purple) in DLDwt (A), DLD BRCA2−/− (B), and SUM149PT (C). Time- and dose-dependent cytotoxicity induced by veliparib in DLDwt (D), DLD BRCA2−/− (E), and SUM149PT (F). Data are presented as mean ± SEM from at least three independent experiments.

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    Figure 4.

    PARP inhibitors differ in their resolution between catalytic inhibition and BM toxicity. BM colony-forming cell (CFC) data were normalized to DMSO controls and are presented as mean with standard errors of total CFCs (erythroid and myeloid lineages) from three independent donors. Cellular PAR levels were determined by ELISA in BM mononuclear cells treated with PARP inhibitors. Data are mean ± SEM from at least four independent experiments.

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    Figure 5.

    PARP1 trapping activity is associated with greater in vitro cytotoxic potency toward multiple cancer cell lines. In vitro cytotoxic IC50s of PARP inhibitors across cancer cell lines compared with inhibition of PAR formation and inhibition of colony formation of BM cells. IC50s for HeyA8, DLD1, and DLD1 BRCA2−/− cells (A), SCLC lines (B), and breast cancer cell lines (C). For cell lines more sensitive than BM, a two-sided Student t test was performed and *, P < 0.05; **, P < 0.01; ***, P < 0.001. Dashed lines are clinical Cmax/min at monotherapy RP2D. Data points are from a minimum of three independent experiments, and mean ± SEM are indicated.

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    Figure 6.

    Antitumor activity and PK/PD for veliparib, olaparib, and talazoparib in SUM149PT xenografts. A, Efficacy plots for SUM149PT xenografts in mice dosed p.o. with PARP inhibitors. PARP inhibitors were administered p.o., qd, or b.i.d. for 42 days (d30–71). Data are presented as mean with standard errors. Maximum percent weight loss and percent tumor growth inhibition (TGI) on day 54 vs. vehicle are indicated. P values are from two-sided t tests for mean difference in log10 (tumor volume) on specified day. B, PK and PD in SUM149PT xenograft tumor-bearing mice. Mice were dosed p.o., b.i.d., or qd as indicated with compounds for 5 days. At 1, 4, 24, 32, and 48 hours after the last dose, plasma and tumors samples were harvested. Plasma and tumor drug concentrations (PK) and tumor PAR levels (PD) were determined. Data are presented as mean with standard errors.

Additional Files

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    • Supplementary Table 1 - IC50s (nM) for inhibition of enzyme activity for PARP family members
    • Supplementary Table 2 - Clinical RP2D concentrations for PARP inhibitors.
    • Supplementary Table 3 - IC50 values of PARPi vs BM-CFU and BM-PAR
    • Supplementary Table 4 - Bone Marrow IC50s broken into cell type.
    • Supplementary Figure 1 - Association of PARP1 and H2A.X detected by Proximity Ligation Assay (PLA).
    • Supplementary Figure 2 - Association of PARP1 and other histone proteins detected by Proximity Ligation Assay (PLA).
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Molecular Cancer Research: 17 (2)
February 2019
Volume 17, Issue 2
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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 February 1 2019 (17) (2) 409-419; 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 February 1 2019 (17) (2) 409-419; DOI: 10.1158/1541-7786.MCR-18-0138
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