title: The caspase-8 inhibitor emricasan combines with the SMAC mimetic birinapant to induce necroptosis and treat acute myeloid leukemia.
abstract: Resistance to chemotherapy is a major problem in cancer treatment, and it is frequently associated with failure of tumor cells to undergo apoptosis. Birinapant, a clinical SMAC mimetic, had been designed to mimic the interaction between inhibitor of apoptosis proteins (IAPs) and SMAC/Diablo, thereby relieving IAP-mediated caspase inhibition and promoting apoptosis of cancer cells. We show that acute myeloid leukemia (AML) cells are sensitive to birinapant-induced death and that the clinical caspase inhibitor emricasan/IDN-6556 augments, rather than prevents, killing by birinapant. Deletion of caspase-8 sensitized AML to birinapant, whereas combined loss of caspase-8 and the necroptosis effector MLKL (mixed lineage kinase domain-like) prevented birinapant/IDN-6556-induced death, showing that inhibition of caspase-8 sensitizes AML cells to birinapant-induced necroptosis. However, loss of MLKL alone did not prevent a caspase-dependent birinapant/IDN-6556-induced death, implying that AML will be less likely to acquire resistance to this drug combination. A therapeutic breakthrough in AML has eluded researchers for decades. Demonstrated antileukemic efficacy and safety of the birinapant/emricasan combination in vivo suggest that induction of necroptosis warrants clinical investigation as a therapeutic opportunity in AML.
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3052, Australia. Department of Medical Biology, University of Melbourne, Melbourne, Victoria 3050, Australia.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Brumatti
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3052, Australia. Department of Medical Biology, University of Melbourne, Melbourne, Victoria 3050, Australia.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Ma
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3052, Australia. Department of Medical Biology, University of Melbourne, Melbourne, Victoria 3050, Australia.
authors.forename: Najoua
authors.initials: N
authors.lastname: Lalaoui
authors.affiliation: Alfred Hospital and Monash University, Melbourne, Victoria 3004, Australia.
authors.forename: Nhu-Y
authors.initials: NY
authors.lastname: Nguyen
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors.forename: Mario
authors.initials: M
authors.lastname: Navarro
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3052, Australia. Department of Medical Biology, University of Melbourne, Melbourne, Victoria 3050, Australia.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Tanzer
authors.affiliation: Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, New South Wales 2031, Australia.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Richmond
authors.affiliation: Peter MacCallum Cancer Centre, Melbourne, Victoria 3002, Australia.
authors.forename: Margherita
authors.initials: M
authors.lastname: Ghisi
authors.affiliation: Peter MacCallum Cancer Centre, Melbourne, Victoria 3002, Australia.
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Salmon
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3052, Australia. Department of Medical Biology, University of Melbourne, Melbourne, Victoria 3050, Australia.
authors.forename: Natasha
authors.initials: N
authors.lastname: Silke
authors.affiliation: Alfred Hospital and Monash University, Melbourne, Victoria 3004, Australia.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Pomilio
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3052, Australia. Department of Medical Biology, University of Melbourne, Melbourne, Victoria 3050, Australia.
authors.forename: Stefan P
authors.initials: SP
authors.lastname: Glaser
authors.affiliation: Burnet Institute, Melbourne, Victoria 3004, Australia. Department of Immunology, Central Clinical School, Monash University, Melbourne, Victoria 3004, Australia.
authors.forename: Elisha
authors.initials: E
authors.lastname: de Valle
authors.affiliation: Burnet Institute, Melbourne, Victoria 3004, Australia. Department of Immunology, Central Clinical School, Monash University, Melbourne, Victoria 3004, Australia.
authors.forename: Raffi
authors.initials: R
authors.lastname: Gugasyan
authors.affiliation: Alfred Hospital and Monash University, Melbourne, Victoria 3004, Australia.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Gurthridge
authors.affiliation: TetraLogic Pharmaceuticals Corporation, Malvern, PA 19355, USA.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Condon
authors.affiliation: Peter MacCallum Cancer Centre, Melbourne, Victoria 3002, Australia.
authors.forename: Ricky W
authors.initials: RW
authors.lastname: Johnstone
authors.affiliation: Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, New South Wales 2031, Australia.
authors.forename: Richard
authors.initials: R
authors.lastname: Lock
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors.forename: Guy
authors.initials: G
authors.lastname: Salvesen
authors.affiliation: Alfred Hospital and Monash University, Melbourne, Victoria 3004, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Wei
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3052, Australia. Department of Medical Biology, University of Melbourne, Melbourne, Victoria 3050, Australia.
authors.forename: David L
authors.initials: DL
authors.lastname: Vaux
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3052, Australia. Department of Medical Biology, University of Melbourne, Melbourne, Victoria 3050, Australia. Murdoch Childrens Research Institute, The Royal Children's Hospital, Melbourne, Victoria 3052, Australia. silke@wehi.edu.au paul.ekert@mcri.edu.au.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Ekert
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3052, Australia. Department of Medical Biology, University of Melbourne, Melbourne, Victoria 3050, Australia. silke@wehi.edu.au paul.ekert@mcri.edu.au.
authors.forename: John
authors.initials: J
authors.lastname: Silke
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D053181:Caspase 8 / Q000378:metabolism*; D061945:Caspase Inhibitors / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004151:Dipeptides / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism; D009336:Necrosis / Q000378:metabolism; D010421:Pentanoic Acids / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: C487112:3-(2-(2-tert-butylphenylaminooxalyl)aminopropionylamino)-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid; D061945:Caspase Inhibitors; D004151:Dipeptides; D007211:Indoles; D047908:Intracellular Signaling Peptides and Proteins; D010421:Pentanoic Acids; C582429:birinapant; D053181:Caspase 8