title: Activation of concurrent apoptosis and necroptosis by SMAC mimetics for the treatment of refractory and relapsed ALL.
abstract: More precise treatment strategies are urgently needed to decrease toxicity and improve outcomes for treatment-refractory leukemia. We used ex vivo drug response profiling of high-risk, relapsed, or refractory acute lymphoblastic leukemia (ALL) cases and identified a subset with exquisite sensitivity to small-molecule mimetics of the second mitochondria-derived activator of caspases (SMAC) protein. Potent ex vivo activity of the SMAC mimetic (SM) birinapant correlated with marked in vivo antileukemic effects, as indicated by delayed engraftment, decreased leukemia burden, and prolonged survival of xenografted mice. Antileukemic activity was dependent on simultaneous execution of apoptosis and necroptosis, as demonstrated by functional genomic dissection with a multicolored lentiCRISPR approach to simultaneously disrupt multiple genes in patient-derived ALL. SM specifically targeted receptor-interacting protein kinase 1 (RIP1)-dependent death, and CRISPR-mediated disruption of RIP1 completely blocked SM-induced death yet had no impact on the response to standard antileukemic agents. Thus, SM compounds such as birinapant circumvent escape from apoptosis in leukemia by activating a potent dual RIP1-dependent apoptotic and necroptotic cell death, which is not exploited by current therapy. Ex vivo drug activity profiling could provide important functional diagnostic information to identify patients who may benefit from targeted treatment with birinapant in early clinical trials.
authors.affiliation: Department of Oncology and Children's Research Centre, University Children's Hospital Zürich, 8032 Zürich, Switzerland.
authors.forename: Scott
authors.initials: S
authors.lastname: McComb
authors.affiliation: Department of Oncology and Children's Research Centre, University Children's Hospital Zürich, 8032 Zürich, Switzerland.
authors.forename: Júlia
authors.initials: J
authors.lastname: Aguadé-Gorgorió
authors.affiliation: Department of Oncology and Children's Research Centre, University Children's Hospital Zürich, 8032 Zürich, Switzerland.
authors.forename: Lena
authors.initials: L
authors.lastname: Harder
authors.affiliation: Department of Oncology and Children's Research Centre, University Children's Hospital Zürich, 8032 Zürich, Switzerland.
authors.forename: Blerim
authors.initials: B
authors.lastname: Marovca
authors.affiliation: Department of General Pediatrics, University Hospital Schleswig-Holstein, 24105 Kiel, Germany.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Cario
authors.affiliation: Department of Pediatric Oncology and Hematology, Charité Medical University Berlin, 13353 Berlin, Germany.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Eckert
authors.affiliation: Department of General Pediatrics, University Hospital Schleswig-Holstein, 24105 Kiel, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Schrappe
authors.affiliation: Pediatric Hematology and Oncology, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Stanulla
authors.affiliation: Department of Pediatric Oncology and Hematology, Charité Medical University Berlin, 13353 Berlin, Germany.
authors.forename: Arend
authors.initials: A
authors.lastname: von Stackelberg
authors.affiliation: Department of Oncology and Children's Research Centre, University Children's Hospital Zürich, 8032 Zürich, Switzerland.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Bourquin
authors.affiliation: Department of Oncology and Children's Research Centre, University Children's Hospital Zürich, 8032 Zürich, Switzerland. beat.bornhauser@kispi.uzh.ch.
authors.forename: Beat C
authors.initials: BC
authors.lastname: Bornhauser
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins; D045744:Cell Line, Tumor; D004151:Dipeptides / Q000494:pharmacology*; D004357:Drug Synergism; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D024101:Mitochondrial Proteins / Q000378:metabolism; D009336:Necrosis / Q000378:metabolism*; D028861:Nuclear Pore Complex Proteins / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C119724:AGFG1 protein, human; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C412403:DIABLO protein, human; D004151:Dipeptides; D007211:Indoles; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D028861:Nuclear Pore Complex Proteins; D016601:RNA-Binding Proteins; D014409:Tumor Necrosis Factor-alpha; C582429:birinapant; C119705:RIPK3 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases