title: Molecular Pathways: The Necrosome-A Target for Cancer Therapy.
abstract: Necroptosis is a caspase-8-independent cell death that requires coactivation of receptor-interacting protein 1 (RIP1) and receptor-interacting protein 3 (RIP3) kinases. The necrosome is a complex consisting of RIP1, RIP3, and Fas-associated protein with death domain leading to activation of the pseudokinase mixed lineage kinase like followed by a rapid plasma membrane rupture and inflammatory response through the release of damage-associated molecular patterns and cytokines. The necrosome has been shown to be relevant in multiple tumor types, including pancreatic adenocarcinoma, melanoma, and several hematologic malignancies. Preclinical data suggest that targeting this complex can have differential impact on tumor progression and that the effect of necroptosis on oncogenesis is cell-type and context dependent. The emerging data suggest that targeting the necrosome may lead to immunogenic reprogramming in the tumor microenvironment in multiple tumors and that combining therapies targeting the necrosome with either conventional chemotherapy or immunotherapy may have beneficial effects. Thus, understanding the interplay of necroptotic cell death, transformed cells, and the immune system may enable the development of novel therapeutic approaches.Clin Cancer Res; 23(5); 1132-6. ©2016 AACR.
authors.affiliation: Department of General, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, University of Dresden, Dresden, Germany.
authors.forename: Lena
authors.initials: L
authors.lastname: Seifert
authors.affiliation: Department of Surgery, S. Arthur Localio Laboratory, New York University School of Medicine, New York, New York. george.miller@nyumc.org.|Department of Cell Biology, S. Arthur Localio Laboratory, New York University School of Medicine, New York, New York.
authors.forename: George
authors.initials: G
authors.lastname: Miller
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D019070:Cell Lineage / Q000187:drug effects; D006801:Humans; D058990:Molecular Targeted Therapy; D046912:Multiprotein Complexes / Q000187:drug effects; D009336:Necrosis / Q000235:genetics / Q000473:pathology; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D028861:Nuclear Pore Complex Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D059016:Tumor Microenvironment / Q000187:drug effects / Q000276:immunology
chemical_list: C119724:AGFG1 protein, human; D046912:Multiprotein Complexes; D028861:Nuclear Pore Complex Proteins; D016601:RNA-Binding Proteins; C119705:RIPK3 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases