Journal article
The caspase-8 inhibitor emricasan combines with the SMAC mimetic birinapant to induce necroptosis and treat acute myeloid leukemia
G Brumatti, C Ma, N Lalaoui, NY Nguyen, M Navarro, MC Tanzer, J Richmond, M Ghisi, JM Salmon, N Silke, G Pomilio, SP Glaser, E De Valle, R Gugasyan, MA Gurthridge, SM Condon, RW Johnstone, R Lock, G Salvesen, A Wei Show all
Science Translational Medicine | AMER ASSOC ADVANCEMENT SCIENCE | Published : 2016
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 effec..
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Awarded by National Institutes of Health
Funding Acknowledgements
This work was supported by a grant from the Leukemia & Lymphoma Society [SCOR (Specialized Center of Research) grant 7001-06 to D.L.V.], the National Health and Medical Research Council (NHMRC; grants 461221, 1025594, 1046010, and 1081376), NHMRC fellowships (grants 541901 and 1058190 to J.S.), and an Association pour le Recherche contre le Cancer (ARC) fellowship to N.L. with additional support from the Australian Cancer Research Foundation, the Victorian State Government Operational Infrastructure Support, and the NHMRC Independent Research Institutes Infrastructure Support Scheme (grant 361646). G.S. and M.N. are supported by NIH (grants RO1GM099040 and 5 R01CA163743). R.L. is supported by an NHMRC fellowship (1059804).