Research ArticleCancer

Activation of concurrent apoptosis and necroptosis by SMAC mimetics for the treatment of refractory and relapsed ALL

Science Translational Medicine  18 May 2016:
Vol. 8, Issue 339, pp. 339ra70
DOI: 10.1126/scitranslmed.aad2986

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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

More precise treatment strategies are urgently needed to decrease toxicity and improve outcomes for treatment-refractory leukemia. We used ex vivo drug response profiling of high-risk, relapsed, or refractory acute lymphoblastic leukemia (ALL) cases and identified a subset with exquisite sensitivity to small-molecule mimetics of the second mitochondria-derived activator of caspases (SMAC) protein. Potent ex vivo activity of the SMAC mimetic (SM) birinapant correlated with marked in vivo antileukemic effects, as indicated by delayed engraftment, decreased leukemia burden, and prolonged survival of xenografted mice. Antileukemic activity was dependent on simultaneous execution of apoptosis and necroptosis, as demonstrated by functional genomic dissection with a multicolored lentiCRISPR approach to simultaneously disrupt multiple genes in patient-derived ALL. SM specifically targeted receptor-interacting protein kinase 1 (RIP1)–dependent death, and CRISPR-mediated disruption of RIP1 completely blocked SM-induced death yet had no impact on the response to standard antileukemic agents. Thus, SM compounds such as birinapant circumvent escape from apoptosis in leukemia by activating a potent dual RIP1-dependent apoptotic and necroptotic cell death, which is not exploited by current therapy. Ex vivo drug activity profiling could provide important functional diagnostic information to identify patients who may benefit from targeted treatment with birinapant in early clinical trials.

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