Stereospecific PARP Trapping by BMN 673 and Comparison with Olaparib and Rucaparib
Tóm tắt
Anti-PARP drugs were initially developed as catalytic inhibitors to block the repair of DNA single-strand breaks. We recently reported that several PARP inhibitors have an additional cytotoxic mechanism by trapping PARP–DNA complexes, and that both olaparib and niraparib act as PARP poisons at pharmacologic concentrations. Therefore, we have proposed that PARP inhibitors should be evaluated based both on catalytic PARP inhibition and PARP–DNA trapping. Here, we evaluated the novel PARP inhibitor, BMN 673, and compared its effects on PARP1 and PARP2 with two other clinical PARP inhibitors, olaparib and rucaparib, using biochemical and cellular assays in genetically modified chicken DT40 and human cancer cell lines. Although BMN 673, olaparib, and rucaparib are comparable at inhibiting PARP catalytic activity, BMN 673 is ∼100-fold more potent at trapping PARP–DNA complexes and more cytotoxic as single agent than olaparib, whereas olaparib and rucaparib show similar potencies in trapping PARP–DNA complexes. The high level of resistance of PARP1/2 knockout cells to BMN 673 demonstrates the selectivity of BMN 673 for PARP1/2. Moreover, we show that BMN 673 acts by stereospecific binding to PARP1 as its enantiomer, LT674, is several orders of magnitude less efficient. BMN 673 is also approximately 100-fold more cytotoxic than olaparib and rucaparib in combination with the DNA alkylating agents methyl methane sulfonate (MMS) and temozolomide. Our study demonstrates that BMN 673 is the most potent clinical PARP inhibitor tested to date with the highest efficiency at trapping PARP–DNA complexes. Mol Cancer Ther; 13(2); 433–43. ©2013 AACR.
Từ khóa
Tài liệu tham khảo
Schreiber, 2006, Poly(ADP-ribose): novel functions for an old molecule, Nat Rev Mol Cell Biol, 7, 517, 10.1038/nrm1963
Hassa, 2008, The diverse biological roles of mammalian PARPS, a small but powerful family of poly-ADP-ribose polymerases, Front Biosci, 13, 3046, 10.2741/2909
Krishnakumar, 2010, The PARP side of the nucleus: molecular actions, physiological outcomes, and clinical targets, Mol Cell, 39, 8, 10.1016/j.molcel.2010.06.017
Banerjee, 2010, Making the best of PARP inhibitors in ovarian cancer, Nat Rev Clin Oncol, 7, 508, 10.1038/nrclinonc.2010.116
Helleday, 2008, DNA repair pathways as targets for cancer therapy, Nat Rev Cancer, 8, 193, 10.1038/nrc2342
Zhang, 2011, Poly(ADP-ribose) polymerase and XPF-ERCC1 participate in distinct pathways for the repair of topoisomerase I-induced DNA damage in mammalian cells, Nucleic Acids Res, 39, 3607, 10.1093/nar/gkq1304
Delaney, 2000, Potentiation of temozolomide and topotecan growth inhibition and cytotoxicity by novel poly(adenosine diphosphoribose) polymerase inhibitors in a panel of human tumor cell lines, Clin Cancer Res, 6, 2860
Ray Chaudhuri, 2012, Topoisomerase I poisoning results in PARP-mediated replication fork reversal, Nat Struct Mol Biol, 19, 417, 10.1038/nsmb.2258
Berti, 2013, Human RECQ1 promotes restart of replication forks reversed by DNA topoisomerase I inhibition, Nat Struct Mol Biol, 20, 347, 10.1038/nsmb.2501
Strumberg, 2000, Conversion of topoisomerase I cleavage complexes on the leading strand of ribosomal DNA into 5′-phosphorylated DNA double-strand breaks by replication runoff, Mol Cell Biol, 20, 3977, 10.1128/MCB.20.11.3977-3987.2000
Helleday, 2011, The underlying mechanism for the PARP and BRCA synthetic lethality: clearing up the misunderstandings, Mol Oncol, 5, 387, 10.1016/j.molonc.2011.07.001
Noel, 2006, Radiosensitization by the poly(ADP-ribose) polymerase inhibitor 4-amino-1,8-naphthalimide is specific of the S phase of the cell cycle and involves arrest of DNA synthesis, Mol Cancer Ther, 5, 564, 10.1158/1535-7163.MCT-05-0418
Saleh-Gohari, 2005, Spontaneous homologous recombination is induced by collapsed replication forks that are caused by endogenous DNA single-strand breaks, Mol Cell Biol, 25, 7158, 10.1128/MCB.25.16.7158-7169.2005
Bryant, 2005, Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase, Nature, 434, 913, 10.1038/nature03443
Farmer, 2005, Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy, Nature, 434, 917, 10.1038/nature03445
Fong, 2009, Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers, N Engl J Med, 361, 123, 10.1056/NEJMoa0900212
Curtin, 2013, Therapeutic applications of PARP inhibitors: anticancer therapy and beyond, Mol Aspects Med, 34, 1217, 10.1016/j.mam.2013.01.006
McCabe, 2006, Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition, Cancer Res, 66, 8109, 10.1158/0008-5472.CAN-06-0140
Ashworth, 2008, A synthetic lethal therapeutic approach: poly(ADP) ribose polymerase inhibitors for the treatment of cancers deficient in DNA double-strand break repair, J Clin Oncol, 26, 3785, 10.1200/JCO.2008.16.0812
Kummar, 2012, Advances in using PARP inhibitors to treat cancer, BMC Med, 10, 25, 10.1186/1741-7015-10-25
Chuang, 2012, Differential anti-proliferative activities of poly(ADP-ribose) polymerase (PARP) inhibitors in triple-negative breast cancer cells, Breast Cancer Res Treat, 134, 649, 10.1007/s10549-012-2106-5
Patel, 2012, Enhanced killing of cancer cells by poly(ADP-ribose) polymerase inhibitors and topoisomerase I inhibitors reflects poisoning of both enzymes, J Biol Chem, 287, 4198, 10.1074/jbc.M111.296475
Murai, 2012, Trapping of PARP1 and PARP2 by clinical PARP inhibitors, Cancer Res, 72, 5588, 10.1158/0008-5472.CAN-12-2753
Hochegger, 2006, Parp-1 protects homologous recombination from interference by Ku and Ligase IV in vertebrate cells, EMBO J, 25, 1305, 10.1038/sj.emboj.7601015
Garnett, 2012, Systematic identification of genomic markers of drug sensitivity in cancer cells, Nature, 483, 570, 10.1038/nature11005
Ji, 2011, Modeling pharmacodynamic response to the poly(ADP-Ribose) polymerase inhibitor ABT-888 in human peripheral blood mononuclear cells, PLoS ONE, 6, e26152, 10.1371/journal.pone.0026152
Division of Cancer Treatment and Diagnosis [Internet]
NCI-60 DTP Human Tumor Cell Line Screen [Internet]
Holbeck, 2010, Analysis of Food and Drug Administration–approved anticancer agents in the NCI60 panel of human tumor cell lines, Mol Cancer Ther, 9, 1451, 10.1158/1535-7163.MCT-10-0106
Holbeck, 2010, Expression profiling of nuclear receptors in the NCI60 cancer cell panel reveals receptor-drug and receptor-gene interactions, Mol Endocrinol, 24, 1287, 10.1210/me.2010-0040
Kummar, 2010, Utilizing targeted cancer therapeutic agents in combination: novel approaches and urgent requirements, Nat Rev Drug Discov, 9, 843, 10.1038/nrd3216
Kummar, 2009, Phase 0 clinical trial of the poly (ADP-ribose) polymerase inhibitor ABT-888 in patients with advanced malignancies, J Clin Oncol, 27, 2705, 10.1200/JCO.2008.19.7681
Hatanaka, 2005, Similar effects of Brca2 truncation and Rad51 paralog deficiency on immunoglobulin V gene diversification in DT40 cells support an early role for Rad51 paralogs in homologous recombination, Mol Cell Biol, 25, 1124, 10.1128/MCB.25.3.1124-1134.2005
Pettitt, 2013, A genetic screen using the PiggyBac transposon in haploid cells identifies Parp1 as a mediator of olaparib toxicity, PLoS ONE, 8, e61520, 10.1371/journal.pone.0061520
Grohar, 2011, Ecteinascidin 743 interferes with the activity of EWS-FLI1 in Ewing sarcoma cells, Neoplasia, 13, 145, 10.1593/neo.101202
Reinhold, 2012, CellMiner: a web-based suite of genomic and pharmacologic tools to explore transcript and drug patterns in the nci-60 cell line set, Cancer Res, 72, 3499, 10.1158/0008-5472.CAN-12-1370
Boulton, 1995, Potentiation of temozolomide-induced cytotoxicity: a comparative study of the biological effects of poly(ADP-ribose) polymerase inhibitors, Br J Cancer, 72, 849, 10.1038/bjc.1995.423
Plummer, 2008, Phase I study of the poly(ADP-ribose) polymerase inhibitor, AG014699, in combination with temozolomide in patients with advanced solid tumors, Clin Cancer Res, 14, 7917, 10.1158/1078-0432.CCR-08-1223
Langelier, 2012, Structural basis for DNA damage-dependent poly(ADP-ribosyl)ation by human PARP-1, Science, 336, 728, 10.1126/science.1216338
Shen, 2013, BMN 673, a novel and highly potent PARP1/2 inhibitor for the treatment of human cancers with DNA repair deficiency, Clin Cancer Re, 19, 5003, 10.1158/1078-0432.CCR-13-1391
Postel-Vinay, 2013, A high-throughput screen identifies PARP1/2 inhibitors as a potential therapy for ERCC1-deficient non–small cell lung cancer, Oncogene, 32, 5377, 10.1038/onc.2013.311
Wahlberg, 2012, Family-wide chemical profiling and structural analysis of PARP and tankyrase inhibitors., Nat Biotechnol, 30, 283, 10.1038/nbt.2121
Chang, 2005, Tankyrase-1 polymerization of poly(ADP-ribose) is required for spindle structure and function, Nat Cell Biol, 7, 1133, 10.1038/ncb1322
Mendes-Pereira, 2009, Synthetic lethal targeting of PTEN mutant cells with PARP inhibitors, Embo Mol Med, 1, 315, 10.1002/emmm.200900041
Bunting, 2010, 53BP1 inhibits homologous recombination in Brca1-deficient cells by blocking resection of DNA breaks, Cell, 141, 243, 10.1016/j.cell.2010.03.012