title: Synthetic Lethality Exploitation by an Anti-Trop-2-SN-38 Antibody-Drug Conjugate, IMMU-132, Plus PARP Inhibitors inBRCA1/2-wild-type Triple-Negative Breast Cancer.
abstract: Purpose:Both PARP inhibitors (PARPi) and sacituzumab govitecan (IMMU-132) are currently under clinical evaluation in triple-negative breast cancer (TNBC). We sought to investigate the combined DNA-damaging effects of the topoisomerase I (Topo I)-inhibitory activity of IMMU-132 with PARPi disruption of DNA repair in TNBC.Experimental Design:In vitro, human TNBC cell lines were incubated with IMMU-132 and various PARPi (olaparib, rucaparib, or talazoparib) to determine the effect on growth, double-stranded DNA (dsDNA) breaks, and cell-cycle arrest. Mice bearingBRCA1/2-mutated or -wild-type human TNBC tumor xenografts were treated with the combination of IMMU-132 and PARPi (olaparib or talazoparib). Study survival endpoint was tumor progression to >1.0 cm3and tolerability assessed by hematologic changes.Results:Combining IMMU-132 in TNBC with all three different PARPi results in synergistic growth inhibition, increased dsDNA breaks, and accumulation of cells in the S-phase of the cell cycle, regardless ofBRCA1/2status. A combination of IMMU-132 plus olaparib or talazoparib produces significantly improved antitumor effects and delay in time-to-tumor progression compared with monotherapy in mice bearingBRCA1/2-mutated HCC1806 TNBC tumors. Furthermore, in mice bearingBRCA1/2-wild-type tumors (MDA-MB-468 or MDA-MB-231), the combination of IMMU-132 plus olaparib imparts a significant antitumor effect and survival benefit above that achieved with monotherapy. Most importantly, this combination was well tolerated, with no substantial changes in hematologic parameters.Conclusions:These data demonstrate the added benefit of combining Topo I inhibition mediated by IMMU-132 with synthetic lethality provided by PARPi in TNBC, regardless ofBRCA1/2status, thus supporting the rationale for such a combination clinically.Clin Cancer Res; 23(13); 3405-15. ©2017 AACR.
authors.affiliation: Immunomedics, Inc., Morris Plains, New Jersey. dmg.gscancer@att.net tcardillo@immunomedics.com.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Cardillo
authors.affiliation: Immunomedics, Inc., Morris Plains, New Jersey.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Sharkey
authors.affiliation: Immunomedics, Inc., Morris Plains, New Jersey.
authors.forename: Diane L
authors.initials: DL
authors.lastname: Rossi
authors.affiliation: Immunomedics, Inc., Morris Plains, New Jersey.
authors.forename: Roberto
authors.initials: R
authors.lastname: Arrojo
authors.affiliation: Immunomedics, Inc., Morris Plains, New Jersey.
authors.forename: Ali A
authors.initials: AA
authors.lastname: Mostafa
authors.affiliation: Immunomedics, Inc., Morris Plains, New Jersey. dmg.gscancer@att.net tcardillo@immunomedics.com.
authors.forename: David M
authors.initials: DM
authors.lastname: Goldenberg
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000276:immunology; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D045744:Cell Line, Tumor; D004260:DNA Repair / Q000187:drug effects; D004264:DNA Topoisomerases, Type I / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018796:Immunoconjugates / Q000008:administration & dosage* / Q000276:immunology; D007211:Indoles / Q000008:administration & dosage; D051379:Mice; D010793:Phthalazines / Q000008:administration & dosage; D010879:Piperazines / Q000008:administration & dosage; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000008:administration & dosage; D000072020:Synthetic Lethal Mutations / Q000235:genetics; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D018796:Immunoconjugates; D007211:Indoles; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C531549:rucaparib; C586365:talazoparib; D004264:DNA Topoisomerases, Type I; C000608132:sacituzumab govitecan; C531550:olaparib; D002166:Camptothecin