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

Brumatti, G; Ma, C; Lalaoui, N; Nguyen, NY; Navarro, M; Tanzer, MC; Richmond, J; Ghisi, M; Salmon, JM; Silke, N; Pomilio, G; Glaser, SP; de Valle, E; Gugasyan, R; Gurthridge, MA; Condon, SM; Johnstone, RW; Lock, R; Salvesen, G; Wei, A; Vaux, DL; Ekert, PG; Silke, J

Author(s): Brumatti, G; Ma, C; Lalaoui, N; Nguyen, NY; Navarro, M; Tanzer, MC; Richmond, J; Ghisi, M; Salmon, JM; Silke, N; Pomilio, G; Glaser, SP; de Valle, E; Gugasyan, R; Gurthridge, MA; Condon, SM; Johnstone, RW; Lock, R; Salvesen, G; Wei, A; Vaux, DL; Ekert, PG; Silke, J;
Details: Publication Year 2016-05-18,Volume 8,Issue #339,Page 339ra69
Journal Title: Sci Transl Med
Publication Type: Journal Article
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.
Publisher: AAAS
Research Division(s): Cell Signalling And Cell Death; Cancer And Haematology
PubMed ID: 27194727
Publisher's Version: https://doi.org/10.1126/scitranslmed.aad3099
NHMRC Grants: NHMRC/461221, NHMRC/1025594, NHMRC/1046010, NHMRC/1081376, NHMRC/541901, NHMRC/1058190,
Terms of Use/Rights Notice: Refer to copyright notice on published article.
Documents: Brumatti_Sci Transl Med_2016.pdf - (2.91MB, application/pdf)

Creation Date: 2016-06-15 12:27:22

Last Modified: 2016-06-15 02:32:07