Research ArticleCancer

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

Science Translational Medicine  18 May 2016:
Vol. 8, Issue 339, pp. 339ra69
DOI: 10.1126/scitranslmed.aad3099

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Giving leukemia a SMAC

Second mitochondria-derived activator of caspases, or SMAC, is a protein involved in apoptosis, a mechanism of cell death that is commonly targeted by cancer therapies. SMAC mimetics are drugs designed to mimic the action of SMAC. Now, a pair of related articles provides insights into the effects of SMAC mimetics in leukemia. For acute lymphocytic leukemia, McComb et al. show that a SMAC mimetic called birinapant works best when it can activate two different types of cell death: apoptosis and necroptosis. For acute myelocytic leukemia, Brumatti et al. show that birinapant is particularly effective when combined with a caspase inhibitor, which shuts off the apoptotic pathway and promotes cell death by necroptosis. These findings should be helpful for identifying patients most likely to benefit from treatment with SMAC mimetics and selecting effective treatment combinations for these patients.

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.

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