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

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PARP1 Trapping by PARP Inhibitors Drives Cytotoxicity Both in Cancer Cells and Healthy Bone Marrow Author Manuscript Published OnlineFirst on November 14, 2018; DOI: 10.1158/1541-7786.MCR-18-0138 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 Title: PARP1 trapping by PARP inhibitors drives cytotoxicity both in cancer 2 cells and healthy bone marrow 3 4 Authors: Todd A. Hopkins, William B. Ainsworth, Paul A. Ellis, Cherrie K. 5 Donawho, Enrico L. DiGiammarino, Sanjay C. Panchal, Vivek C. 6 Abraham, Mikkel A. Algire, Yan Shi, Amanda M. Olson, Eric F. Johnson, 7 Julie L. Wilsbacher, David Maag* 8 9 Author affiliations: AbbVie, Inc., North Chicago, Illinois, USA 10 Running title: PARP trapping: impact on in vivo activity of PARP inhibitors 11 Keywords: PARP, DNA damage, veliparib,talazoparib, rucaparib, A-934935 12 Financial support: This work was financially supported by AbbVie, Inc. 13 Corresponding author: *David Maag, Oncology Development, AbbVie, Inc., 1 N. Waukegan 14 Road, North Chicago, Illinois, USA 60064. Phone: 847-937-3969; E- 15 mail: [email protected]. 16 Disclosure: All authors are employees of AbbVie. The design, study conduct, and 17 financial support for this research were provided by AbbVie. AbbVie 18 participated in the interpretation of data, review, and approval of the 19 publication. 20 Word count: 5163/5000 21 Total number of figures and tables: 12 (6 plus 6 supplemental) 22 1 Downloaded from mcr.aacrjournals.org on September 26, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on November 14, 2018; DOI: 10.1158/1541-7786.MCR-18-0138 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 23 24 Abstract 25 Poly (ADP-ribose) polymerase (PARP) inhibitors have recently been approved as 26 monotherapies for the treatment of recurrent ovarian cancer and metastatic BRCA-associated 27 breast cancer, and ongoing studies are exploring additional indications and combinations with 28 other agents. PARP inhibitors trap PARP onto damaged chromatin when combined with 29 temozolomide and methyl methanesulfonate, but the clinical relevance of these findings 30 remains unknown. PARP trapping has thus far been undetectable in cancer cells treated with 31 PARP inhibitors alone. Here we evaluate the contribution of PARP trapping to the tolerability 32 and efficacy of PARP inhibitors in the monotherapy setting. We developed a novel 33 implementation of the proximity ligation assay to detect chromatin-trapped PARP1 at single- 34 cell resolution with higher sensitivity and throughput than previously reported methods. We 35 further demonstrate that the PARP inhibitor-induced trapping appears to drive single-agent 36 cytotoxicity in healthy human bone marrow, indicating that the toxicity of trapped PARP 37 complexes is not restricted to cancer cells with homologous recombination deficiency (HRD). 38 Finally, we show that PARP inhibitors with dramatically different trapping potencies exhibit 39 comparable tumor growth inhibition at maximum tolerated doses in a xenograft model of 40 BRCA1-mutant triple negative breast cancer. These results are consistent with emerging clinical 41 data and suggest that the inverse relationship between trapping potency and tolerability may 42 limit the potential therapeutic advantage of potent trapping activity. 43 44 Implications: PARP trapping contributes to single-agent cytotoxicity of PARP inhibitors in both 45 cancer cells and healthy bone marrow, and the therapeutic advantage of potent trapping 46 activity appears to be limited. 47 48 49 50 51 2 Downloaded from mcr.aacrjournals.org on September 26, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on November 14, 2018; DOI: 10.1158/1541-7786.MCR-18-0138 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 52 INTRODUCTION 53 The recent approvals of the poly (ADP-ribose) polymerase (PARP) inhibitors olaparib 54 (Lynparza) and rucaparib (Rubraca) for the treatment of BRCA-mutated ovarian cancer (1) and 55 niraparib (Zejula) for the treatment of recurrent ovarian cancer with or without BRCA mutation 56 (2) are important benchmarks in over 50 years of research since the initial discovery of this 57 important class of enzymes. The enzymatic function of PARP1, known as PARylation, is the 58 synthesis of ADP-ribose polymers (PAR) that covalently modify host proteins or its own 59 automodification domain (3). When DNA is damaged, PARP1 binds the damage site and 60 catalyzes synthesis of PAR that recruits host DNA repair proteins. AutoPARylation of PARP1 61 induces an electrostatic destabilization and dissociation from the DNA damage site which 62 enables repair proteins to localize to the lesion (4,5). As a result, DNA damage is repaired and 63 cell viability is maintained. When DNA damage occurs in the presence of a PARP inhibitor, 64 PARP1 binds to damage sites and remains tightly bound or trapped onto the chromatin. 65 PARylation is inhibited and PARP1 remains bound to the lesion, which progresses to replication 66 fork collapse and DNA double strand breaks (DSB) (6). In homologous recombination (HR) 67 competent cells, DNA damage is repaired by the HR pathway and cells remain viable. In HR 68 defective (HRD) cells such as BRCA 1/2 mutants, DSB damage is not repaired with high fidelity, 69 resulting in cell death. The cytotoxicity induced by the combination of HRD and PARP inhibitors 70 is known as synthetic lethality (1). 71 There are now more than 150 completed, running or planned registered trials for the 72 PARP inhibitors niraparib, olaparib, rucaparib, talazoparib and veliparib (www.clinicaltrials.gov). 73 The majority of these trials are monotherapy studies in patients with tumors harboring DNA 74 repair defects while the remaining trials are combinations with chemotherapies including 75 platinums, taxanes, ATM inhibitors, ATR inhibitors, Wee1 inhibitors and PI3K inhibitors as well 76 as with immune-oncology therapies. The role of PARP trapping in the efficacy of clinical PARP 77 inhibitors is under intensive investigation. In vitro studies in DT40 cells showed that all five 78 clinical PARP inhibitors were able to potentiate DNA damage induced by alkylating agents and 79 knockout of PARP1 eliminated this effect (7,8). Although there is only a 40-fold difference in 80 IC50s between the most potent (talazoparib) and least potent (veliparib) compound in catalytic 3 Downloaded from mcr.aacrjournals.org on September 26, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on November 14, 2018; DOI: 10.1158/1541-7786.MCR-18-0138 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 81 inhibition studies, the difference in PARP trapping activity between the inhibitors was greater 82 than 10000-fold (9). This differential trapping potency was theorized to be the result of an 83 allosteric change in protein conformation induced by the more potent trapping agents (7,8); 84 however, we found no evidence of allostery after rigorous biochemical testing (9). Thus, the 85 underlying mechanism behind the high trapping potency of talazoparib relative to other PARP 86 inhibitors remains to be determined. 87 The importance of PARP trapping to the cytotoxic mechanism of PARP inhibitors 88 appears to be context dependent. While the activity of PARP inhibitor combinations with 89 temozolomide appear to be mediated largely by PARP trapping, in the context of combinations 90 with other DNA damaging agents like platinums and irinotecan, efficacy appears to be less 91 dependent on PARP1 trapping (10). The importance of PARP1 trapping in the monotherapy 92 setting remains equivocal. Genetic evidence and correlations with preclinical and clinical 93 maximum tolerated doses (MTDs) suggest that trapping occurs in this context (7-9), but it has 94 yet to be demonstrated directly. 95 In this study, we sought to better understand the effects of PARP1 trapping on PARP 96 inhibitor tolerability and efficacy in the monotherapy setting. To assess the properties of PARP 97 inhibitors that contribute to efficient trapping, we characterized a panel of compounds with 98 similar catalytic potencies and PARP binding residence times to the potent PARP trapping agent 99 talazoparib. This includes the first reported characterization of a novel PARP inhibitor, A- 100 934935. Utilizing a highly sensitive proximity ligation assay (PLA), we were able to detect 101 chromatin-trapped PARP at single cell resolution following single agent PARP inhibitor 102 treatment. Kinetics of PARP trapping relative to PAR inhibition, DNA damage induction, and 103 apoptosis were also analyzed. In addition, PARP inhibitor cytotoxicity was determined in bone 104 marrow progenitors to evaluate contributions of trapping to bone marrow toxicity observed in 105 the clinic. Our data suggest an inverse relationship between PARP inhibitor trapping potency 106 and tolerability due to cytotoxicity within normal cells, and provide important context for 107 translation of reported in vitro trapping activity differences to clinical outcomes. 108 4 Downloaded from mcr.aacrjournals.org on September 26, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on November 14, 2018; DOI: 10.1158/1541-7786.MCR-18-0138 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 109 110 MATERIALS AND METHODS 111 Cell culture 112 HeyA8 cells purchased from M.D. Anderson were maintained in RPMI 1640 with 10% -/- 113 FBS at 5% CO2 and 37°C. Isogenic DLD1 and DLD1-BRCA2 cells with homozygous deletion of 114 exon 11 of BRCA2 were maintained in RPMI 1640 with 10% FBS at 5% CO2 and 37°C. Isogenic 115 haploid cell line HAP1 and HAP1 PARP1 knockout cells were maintained in Iscove’s Modified 116 Dulbecco’s Medium (IMDM) with 10% FBS at 5% CO2 and 37°C. DLD1 and HAP1 lines were 117 licensed from Horizon Discovery, Ltd. (Cambridge, UK). Cell lines H69, H1048, H1930, H2081, 118 T47D, UACC812 and MDA-MB-436 were purchased from ATCC.
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