title: Combining ABCG2 Inhibitors with IMMU-132, an Anti-Trop-2 Antibody Conjugate of SN-38, Overcomes Resistance to SN-38 in Breast and Gastric Cancers.
abstract: Sacituzumab govitecan (IMMU-132), an SN-38-conjugated antibody-drug conjugate, is showing promising therapeutic results in a phase I/II trial of patients with advanced Trop-2-expressing, metastatic, solid cancers. As members of the ATP-binding cassette (ABC) transporters confer chemotherapy resistance by active drug efflux, which is a frequent cause of treatment failure, we explored the use of known inhibitors of ABC transporters for improving the therapeutic efficacy of IMMU-132 by overcoming SN-38 resistance. Two human tumor cell lines made resistant to SN-38, MDA-MB-231-S120 (human breast cancer) and NCI-N87-S120 (human gastric cancer), were established by continuous exposure of the parental cells to stepwise increased concentrations of SN-38 and analyzed by flow cytometry for functional activities of ABCG2 and ABCB1, immunoblotting and qRT-PCR for the expression of ABCG2 at both protein and mRNA levels, and MTS assays for the potency of SN-38 alone or in combination with a modulator of ABC transporters. MDA-MB-231-S120 and NCI-N87-S120 displayed reduced sensitivity to SN-38 in vitro, with IC50 values approximately 50-fold higher than parental MDA-MB-231 and NCI-N87 cells. The increase in drug resistance of both S120 cell populations is associated with the expression of functional ABCG2, but not ABCB1. Importantly, treatment of both S120 sublines with known ABCG2 inhibitors (fumitremorgin C, Ko143, and YHO-13351) restored toxicity of SN-38, and the combination of YHO-13351 with IMMU-132 increased the median survival of mice bearing NCI-N87-S120 xenografts. These results provide a rationale for combination therapy of IMMU-132 and inhibitors of ABC transporters, such as YHO-13351. Mol Cancer Ther; 15(8); 1910-9. ©2016 AACR.
authors.affiliation: Immunomedics, Inc. Morris Plains, New Jersey.
authors.forename: Chien-Hsing
authors.initials: CH
authors.lastname: Chang
authors.affiliation: Immunomedics, Inc. Morris Plains, New Jersey.
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Immunomedics, Inc. Morris Plains, New Jersey.
authors.forename: Maria
authors.initials: M
authors.lastname: Zalath
authors.affiliation: Immunomedics, Inc. Morris Plains, New Jersey.
authors.forename: Donglin
authors.initials: D
authors.lastname: Liu
authors.affiliation: Immunomedics, Inc. Morris Plains, New Jersey.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Cardillo
authors.affiliation: Immunomedics, Inc. Morris Plains, New Jersey. dmg@immunomedics.com.
authors.forename: David M
authors.initials: DM
authors.lastname: Goldenberg
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression; D006801:Humans; D018796:Immunoconjugates / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D000077146:Irinotecan; D051379:Mice; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000951:Antigens, Neoplasm; D015815:Cell Adhesion Molecules; D018796:Immunoconjugates; C499380:TACSTD2 protein, human; D000077146:Irinotecan; C000608132:sacituzumab govitecan; D002166:Camptothecin