title: Tumor cells chronically treated with a trastuzumab-maytansinoid antibody-drug conjugate develop varied resistance mechanisms but respond to alternate treatments.
abstract: Antibody-drug conjugates (ADC) are emerging as clinically effective therapy. We hypothesized that cancers treated with ADCs would acquire resistance mechanisms unique to immunoconjugate therapy and that changing ADC components may overcome resistance. Breast cancer cell lines were exposed to multiple cycles of anti-Her2 trastuzumab-maytansinoid ADC (TM-ADC) at IC80 concentrations followed by recovery. The resistant cells, 361-TM and JIMT1-TM, were characterized by cytotoxicity, proteomic, transcriptional, and other profiling. Approximately 250-fold resistance to TM-ADC developed in 361-TM cells, and cross-resistance was observed to other non-cleavable-linked ADCs. Strikingly, these 361-TM cells retained sensitivity to ADCs containing cleavable mcValCitPABC-linked auristatins. In JIMT1-TM cells, 16-fold resistance to TM-ADC developed, with cross-resistance to other trastuzumab-ADCs. Both 361-TM and JIMT1-TM cells showed minimal resistance to unconjugated mertansine (DM1) and other chemotherapeutics. Proteomics and immunoblots detected increased ABCC1 (MRP1) drug efflux protein in 361-TM cells, and decreased Her2 (ErbB2) in JIMT1-TM cells. Proteomics also showed alterations in various pathways upon chronic exposure to the drug in both cell models. Tumors derived from 361-TM cells grew in mice and were refractory to TM-ADC compared with parental cells. Hence, acquired resistance to trastuzumab-maytansinoid ADC was generated in cultured cancer cells by chronic drug treatment, and either increased ABCC1 protein or reduced Her2 antigen were primary mediators of resistance. These ADC-resistant cell models retain sensitivity to other ADCs or standard-of-care chemotherapeutics, suggesting that alternate therapies may overcome acquired ADC resistance. Mol Cancer Ther; 14(4); 952-63. ©2015 AACR.
authors: Pfizer Oncology, Pearl River, New York. frank.loganzo@pfizer.com.
authors: Frank
authors: F
authors: Loganzo
authors: Pfizer Oncology, Pearl River, New York.
authors: Xingzhi
authors: X
authors: Tan
authors: Pfizer Oncology, Pearl River, New York.
authors: Matthew
authors: M
authors: Sung
authors: Pfizer Oncology, Pearl River, New York.
authors: Guixian
authors: G
authors: Jin
authors: Pfizer Oncology, Pearl River, New York.
authors: Jeremy S
authors: JS
authors: Myers
authors: Pfizer Oncology, Pearl River, New York.
authors: Eugene
authors: E
authors: Melamud
authors: Pfizer Oncology, Pearl River, New York.
authors: Fang
authors: F
authors: Wang
authors: Pfizer Oncology, Andover, Massachusetts.
authors: Veronica
authors: V
authors: Diesl
authors: Pfizer Oncology, Pearl River, New York.
authors: Maximillian T
authors: MT
authors: Follettie
authors: Pfizer Oncology, Pearl River, New York.
authors: Sylvia
authors: S
authors: Musto
authors: Pfizer Oncology, Pearl River, New York.
authors: My-Hanh
authors: MH
authors: Lam
authors: Pfizer Oncology, Pearl River, New York.
authors: William
authors: W
authors: Hu
authors: Pfizer Oncology, Pearl River, New York.
authors: Manoj B
authors: MB
authors: Charati
authors: Pfizer Oncology, Pearl River, New York.
authors: Kiran
authors: K
authors: Khandke
authors: Pfizer Oncology, Pearl River, New York.
authors: Kenny Sung Kyoo
authors: KS
authors: Kim
authors: Pfizer Oncology, Pearl River, New York.
authors: Mike
authors: M
authors: Cinque
authors: Pfizer Oncology, Pearl River, New York.
authors: Judy
authors: J
authors: Lucas
authors: Pfizer World Wide Medicinal Chemistry, Groton, Connecticut.
authors: Edmund
authors: E
authors: Graziani
authors: Pfizer World Wide Medicinal Chemistry, Groton, Connecticut.
authors: Andreas
authors: A
authors: Maderna
authors: Pfizer World Wide Medicinal Chemistry, Groton, Connecticut.
authors: Christopher J
authors: CJ
authors: O'Donnell
authors: Pfizer Oncology, Pearl River, New York.
authors: Kim T
authors: KT
authors: Arndt
authors: Pfizer Oncology, Pearl River, New York.
authors: Hans-Peter
authors: HP
authors: Gerber
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D018796:Immunoconjugates / Q000008:administration & dosage / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D051379:Mice; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport; D020543:Proteome; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction; D059467:Transcriptome; D000068878:Trastuzumab / Q000008:administration & dosage / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000954:Antigens, Surface; D000970:Antineoplastic Agents; D018796:Immunoconjugates; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D020543:Proteome; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C421109:multidrug resistance-associated protein 1