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: 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 Salvesen, Andrew Wei, David L Vaux, Paul G Ekert, John Silke
• Journal: Science translational medicine (Sci Transl Med) Vol. 8 Issue 339 Pg. 339ra69 (05 18 2016) ISSN: 1946-6242 [Electronic] United States
• PMID: 27194727 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016, American Association for the Advancement of Science.

Chemical References

• 3-(2-(2-tert-butylphenylaminooxalyl)aminopropionylamino)-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid
• Caspase Inhibitors
• Dipeptides
• Indoles
• Intracellular Signaling Peptides and Proteins
• Pentanoic Acids
• birinapant
• Caspase 8

Topics

• Apoptosis (drug effects)
• Caspase 8 (metabolism)
• Caspase Inhibitors (pharmacology)
• Cell Line, Tumor
• Dipeptides (pharmacology)
• Drug Resistance, Neoplasm (drug effects)
• Drug Synergism
• Humans
• Indoles (pharmacology)
• Intracellular Signaling Peptides and Proteins
• Leukemia, Myeloid, Acute (metabolism)
• Necrosis (metabolism)
• Pentanoic Acids (pharmacology)
• Tumor Cells, Cultured