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

Gabriela Brumatti, Chunyan Ma, Najoua Lalaoui, Nhu Y. Nguyen, Mario Navarro, Maria C Tanzer, Jennifer Richmond, Margherita Ghisi, Jessica M. Salmon, Natasha Silke, Giovanna Pomilio, Stefan P Glaser, Elisha de Valle, Raffi Gugasyan, Mark A. Gurthridge, Stephen M Condon, Ricky W Johnstone, Richard Lock, Guy S Salvesen, Andrew Wei & 3 others David L. Vaux, Paul G Ekert, John Silke

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Article number339ra69
JournalScience Translational Medicine
Volume8
Issue number339
DOIs
Publication statusPublished - 18 May 2016

Cite this

Brumatti, Gabriela ; Ma, Chunyan ; Lalaoui, Najoua ; Nguyen, Nhu Y. ; Navarro, Mario ; Tanzer, Maria C ; Richmond, Jennifer ; Ghisi, Margherita ; Salmon, Jessica M. ; Silke, Natasha ; Pomilio, Giovanna ; Glaser, Stefan P ; de Valle, Elisha ; Gugasyan, Raffi ; Gurthridge, Mark A. ; Condon, Stephen M ; Johnstone, Ricky W ; Lock, Richard ; Salvesen, Guy S ; Wei, Andrew ; Vaux, David L. ; Ekert, Paul G ; Silke, John. / The caspase-8 inhibitor emricasan combines with the SMAC mimetic birinapant to induce necroptosis and treat acute myeloid leukemia. In: Science Translational Medicine. 2016 ; Vol. 8, No. 339.
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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.",
author = "Gabriela Brumatti and Chunyan Ma and Najoua Lalaoui and Nguyen, {Nhu Y.} and Mario Navarro and Tanzer, {Maria C} and Jennifer Richmond and Margherita Ghisi and Salmon, {Jessica M.} and Natasha Silke and Giovanna Pomilio and Glaser, {Stefan P} and {de Valle}, Elisha and Raffi Gugasyan and Gurthridge, {Mark A.} and Condon, {Stephen M} and Johnstone, {Ricky W} and Richard Lock and Salvesen, {Guy S} and Andrew Wei and Vaux, {David L.} and Ekert, {Paul G} and John Silke",
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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, GS, Wei, A, Vaux, DL, Ekert, PG & Silke, J 2016, 'The caspase-8 inhibitor emricasan combines with the SMAC mimetic birinapant to induce necroptosis and treat acute myeloid leukemia', Science Translational Medicine, vol. 8, no. 339, 339ra69. https://doi.org/10.1126/scitranslmed.aad3099

The caspase-8 inhibitor emricasan combines with the SMAC mimetic birinapant to induce necroptosis and treat acute myeloid leukemia. / Brumatti, Gabriela; Ma, Chunyan; Lalaoui, Najoua; Nguyen, Nhu Y.; Navarro, Mario; Tanzer, Maria C; Richmond, Jennifer; Ghisi, Margherita; Salmon, Jessica M.; Silke, Natasha; Pomilio, Giovanna; Glaser, Stefan P; de Valle, Elisha; Gugasyan, Raffi; Gurthridge, Mark A.; Condon, Stephen M; Johnstone, Ricky W; Lock, Richard; Salvesen, Guy S; Wei, Andrew; Vaux, David L.; Ekert, Paul G; Silke, John.

In: Science Translational Medicine, Vol. 8, No. 339, 339ra69, 18.05.2016.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - The caspase-8 inhibitor emricasan combines with the SMAC mimetic birinapant to induce necroptosis and treat acute myeloid leukemia

AU - Brumatti, Gabriela

AU - Ma, Chunyan

AU - Lalaoui, Najoua

AU - Nguyen, Nhu Y.

AU - Navarro, Mario

AU - Tanzer, Maria C

AU - Richmond, Jennifer

AU - Ghisi, Margherita

AU - Salmon, Jessica M.

AU - Silke, Natasha

AU - Pomilio, Giovanna

AU - Glaser, Stefan P

AU - de Valle, Elisha

AU - Gugasyan, Raffi

AU - Gurthridge, Mark A.

AU - Condon, Stephen M

AU - Johnstone, Ricky W

AU - Lock, Richard

AU - Salvesen, Guy S

AU - Wei, Andrew

AU - Vaux, David L.

AU - Ekert, Paul G

AU - Silke, John

PY - 2016/5/18

Y1 - 2016/5/18

N2 - 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.

AB - 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.

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U2 - 10.1126/scitranslmed.aad3099

DO - 10.1126/scitranslmed.aad3099

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