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Sci Transl Med. 2016 May 18;8(339):339ra69. doi: 10.1126/scitranslmed.aad3099.

The caspase-8 inhibitor emricasan combines with the SMAC mimetic birinapant to induce necroptosis and treat acute myeloid leukemia.

Author information

1
Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3052, Australia. Department of Medical Biology, University of Melbourne, Melbourne, Victoria 3050, Australia.
2
Alfred Hospital and Monash University, Melbourne, Victoria 3004, Australia.
3
Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
4
Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, New South Wales 2031, Australia.
5
Peter MacCallum Cancer Centre, Melbourne, Victoria 3002, Australia.
6
Burnet Institute, Melbourne, Victoria 3004, Australia. Department of Immunology, Central Clinical School, Monash University, Melbourne, Victoria 3004, Australia.
7
TetraLogic Pharmaceuticals Corporation, Malvern, PA 19355, USA.
8
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.
9
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.

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.

PMID:
27194727
DOI:
10.1126/scitranslmed.aad3099
[Indexed for MEDLINE]

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