title: EZN-2208 (PEG-SN38) overcomes ABCG2-mediated topotecan resistance in BRCA1-deficient mouse mammary tumors.
abstract: BRCA1 dysfunction in hereditary breast cancer causes defective homology-directed DNA repair and sensitivity towards DNA damaging agents like the clinically used topoisomerase I inhibitors topotecan and irinotecan. Using our conditional K14cre;Brca1(F/F);p53(F/F) mouse model, we showed previously that BRCA1;p53-deficient mammary tumors initially respond to topotecan, but frequently acquire resistance by overexpression of the efflux transporter ABCG2. Here, we tested the pegylated SN38 compound EZN-2208 as a novel approach to treat BRCA1-mutated tumors that express ABCG2. We found that EZN-2208 therapy resulted in more pronounced and durable responses of ABCG2-positive tumors than topotecan or irinotecan therapy. We also evaluated tumor-specific ABCG2 inhibition by Ko143 in Abcg2(-/-) host animals that carried tumors with topotecan-induced ABCG2 expression. Addition of Ko143 moderately increased overall survival of these animals, but did not yield tumor responses like those seen after EZN-2208 therapy. Our results suggest that pegylation of Top1 inhibitors may be a useful strategy to circumvent efflux transporter-mediated resistance and to improve their efficacy in the clinic.
authors.affiliation: Division of Molecular Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Serge A L
authors.initials: SA
authors.lastname: Zander
authors.forename: Wendy
authors.initials: W
authors.lastname: Sol
authors.forename: Lee
authors.initials: L
authors.lastname: Greenberger
authors.forename: Yixian
authors.initials: Y
authors.lastname: Zhang
authors.forename: Olaf
authors.initials: O
authors.lastname: van Tellingen
authors.forename: Jos
authors.initials: J
authors.lastname: Jonkers
authors.forename: Piet
authors.initials: P
authors.lastname: Borst
authors.forename: Sven
authors.initials: S
authors.lastname: Rottenberg
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000172:deficiency / Q000235:genetics*; D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D019313:BRCA1 Protein / Q000172:deficiency / Q000235:genetics*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D054659:Diketopiperazines; D005260:Female; D015870:Gene Expression; D006576:Heterocyclic Compounds, 4 or More Rings; D000077146:Irinotecan; D008321:Mammary Glands, Animal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D011092:Polyethylene Glycols / Q000494:pharmacology* / Q000627:therapeutic use; D015996:Survival Rate; D059004:Topoisomerase I Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D019772:Topotecan / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: C541506:3-(6-isobutyl-9-methoxy-1,4-dioxo-1,2,3,4,6,7,12,12a-octahydropyrazino(1',2'-1,6)pyrido(3,4-b)indol-3-yl)propionic acid tert-butyl ester; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C501412:Abcg2 protein, mouse; D000970:Antineoplastic Agents; D019313:BRCA1 Protein; D054659:Diketopiperazines; C528970:EZN-2208; D006576:Heterocyclic Compounds, 4 or More Rings; D059004:Topoisomerase I Inhibitors; D011092:Polyethylene Glycols; D000077146:Irinotecan; D019772:Topotecan; D004264:DNA Topoisomerases, Type I; D000241:Adenosine; D002166:Camptothecin