title: Pre-activation of the p53 pathway through Nutlin-3a sensitises sarcomas to drozitumab therapy.
abstract: The present study evaluated the efficacy of drozitumab, a human monoclonal agonistic antibody directed against death receptor 5 (DR5), as a new therapeutic avenue for the targeted treatment of bone and soft-tissue sarcomas. The antitumour activity of drozitumab as a monotherapy or in combination with Nutlin-3a was evaluated in a panel of sarcoma cell lines in vitro and human sarcoma patient samples ex vivo. Knockdown experiments were used to investigate the central role of p53 as a regulator of drozitumab cytotoxicity. Pre-activation of the p53 pathway through Nutlin-3a upregulated DR5, subsequently sensitising sarcoma cell lines and human sarcoma specimens to the pro-apoptotic effects of drozitumab. Silencing of p53 strongly decreased DR5 mRNA expression resulting in abrogation of drozitumab-induced apoptosis. Our study provides the first pre-clinical evaluation of combination therapy using p53-activating agents with drozitumab to further sensitise sarcomas to the cytotoxic effects of DR5 antibody therapy.
authors.affiliation: Centre for Personalised Cancer Medicine, The University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Kathleen I
authors.initials: KI
authors.lastname: Pishas
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Neuhaus
authors.forename: Mark T
authors.initials: MT
authors.lastname: Clayer
authors.forename: Alaknanda
authors.initials: A
authors.lastname: Adwal
authors.forename: Michael P
authors.initials: MP
authors.lastname: Brown
authors.forename: Andreas
authors.initials: A
authors.lastname: Evdokiou
authors.forename: David F
authors.initials: DF
authors.lastname: Callen
authors.forename: Paul M
authors.initials: PM
authors.lastname: Neilsen
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D006801:Humans; D007093:Imidazoles / Q000378:metabolism*; D010879:Piperazines / Q000378:metabolism*; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis; D034741:RNA, Small Interfering; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D012509:Sarcoma / Q000188:drug therapy* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007093:Imidazoles; D010879:Piperazines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3; C548876:drozitumab