title: Doxorubicin overcomes resistance to drozitumab by antagonizing Inhibitor of Apoptosis Proteins (IAPs).
abstract: OBJECTIVE
  Drozitumab is a fully human agonistic monoclonal antibody that binds to death receptor DR5 and induces apoptosis. However, drozitumab resistance is a major obstacle limiting anticancer efficacy.
  
  
  METHODS
  We examined the potential for the chemotherapeutic agent doxorubicin to overcome resistance against drozitumab-resistant breast cancer cells both in vitro and in vivo.
  
  
  RESULTS
  Treatment with doxorubicin increased cell surface expression of DR5, reduced levels of Inhibitors of Apoptosis Proteins (cIAPs) and re-sensitised cells to drozitumab-induced apoptosis. Animals implanted with resistant breast cancer cells into the mammary fat pad and treated with a combination of drozitumab and doxorubicin showed inhibition of tumor growth and a substantial delay in tumor progression compared to untreated controls and mice treated with each agent alone.
  
  
  CONCLUSIONS
  These results suggest that combination of drozitumab with chemotherapy and agents that modulate IAP levels could potentially be a useful strategy in the treatment of breast cancer.
authors.affiliation: Discipline of Surgery, Breast Cancer Research Unit, Basil Hetzel Institute and Centre for Personalised Cancer Medicine, University of Adelaide, Adelaide, SA, Australia.
authors.forename: Irene
authors.initials: I
authors.lastname: Zinonos
authors.affiliation: Discipline of Surgery, Breast Cancer Research Unit, Basil Hetzel Institute and Centre for Personalised Cancer Medicine, University of Adelaide, Adelaide, SA, Australia.
authors.forename: Agatha
authors.initials: A
authors.lastname: Labrinidis
authors.affiliation: Discipline of Surgery, Breast Cancer Research Unit, Basil Hetzel Institute and Centre for Personalised Cancer Medicine, University of Adelaide, Adelaide, SA, Australia.
authors.forename: Vasilios
authors.initials: V
authors.lastname: Liapis
authors.affiliation: Discipline of Surgery, Breast Cancer Research Unit, Basil Hetzel Institute and Centre for Personalised Cancer Medicine, University of Adelaide, Adelaide, SA, Australia.
authors.forename: Shelley
authors.initials: S
authors.lastname: Hay
authors.affiliation: Discipline of Surgery, Breast Cancer Research Unit, Basil Hetzel Institute and Centre for Personalised Cancer Medicine, University of Adelaide, Adelaide, SA, Australia.
authors.forename: Vasilios
authors.initials: V
authors.lastname: Panagopoulos
authors.affiliation: Discipline of Surgery, Breast Cancer Research Unit, Basil Hetzel Institute and Centre for Personalised Cancer Medicine, University of Adelaide, Adelaide, SA, Australia.
authors.forename: Mark
authors.initials: M
authors.lastname: Denichilo
authors.affiliation: Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, NY, U.S.A.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Ponomarev
authors.affiliation: Discipline of Surgery, Haematology - Oncology, Breast Biology Cancer Unit, Basil Hetzel Institute, University of Adelaide, Adelaide, SA, Australia.
authors.forename: Wendy
authors.initials: W
authors.lastname: Ingman
authors.affiliation: Discipline of Orthopaedics and Trauma, University of Adelaide, Adelaide, SA, Australia.
authors.forename: Gerald J
authors.initials: GJ
authors.lastname: Atkins
authors.affiliation: Discipline of Orthopaedics and Trauma, University of Adelaide, Adelaide, SA, Australia.
authors.forename: David M
authors.initials: DM
authors.lastname: Findlay
authors.affiliation: Myeloma Research Laboratory, School of Medical Sciences, Faculty of Health Science and Centre for Personalised Cancer Medicine, University of Adelaide, Adelaide, SA, Australia.
authors.forename: Andrew C W
authors.initials: AC
authors.lastname: Zannettino
authors.affiliation: Discipline of Surgery, Breast Cancer Research Unit, Basil Hetzel Institute and Centre for Personalised Cancer Medicine, University of Adelaide, Adelaide, SA, Australia andreas.evdokiou@adelaide.edu.au.
authors.forename: Andreas
authors.initials: A
authors.lastname: Evdokiou
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D005260:Female; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors*; D051379:Mice; D008819:Mice, Nude; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000096:biosynthesis*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000903:Antibiotics, Antineoplastic; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D051034:Inhibitor of Apoptosis Proteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D004317:Doxorubicin; C548876:drozitumab
keywords: Apo2L/TRAIL; Apoptosis; breast cancer; chemotherapy; drozitumab; drug resistance