title: The SMAC mimetic, LCL-161, reduces survival in aggressive MYC-driven lymphoma while promoting susceptibility to endotoxic shock.
abstract: Inhibitor of apoptosis proteins (IAPs) antagonize caspase activation and regulate death receptor signaling cascades. LCL-161 is a small molecule second mitochondrial activator of caspase (SMAC) mimetic, which both disengages IAPs from caspases and induces proteasomal degradation of cIAP-1 and -2, resulting in altered signaling through the NFκB pathway, enhanced TNF production and sensitization to apoptosis mediated by the extrinsic pathway. SMAC mimetics are undergoing clinical evaluation in a range of hematological malignancies. Burkitt-like lymphomas are hallmarked by a low apoptotic threshold, conveying sensitivity to a range of apoptosis-inducing stimuli. While evaluating LCL-161 in the Eμ-Myc model of aggressive Burkitt-like lymphoma, we noted unexpected resistance to apoptosis induction despite 'on-target' IAP degradation and NFκB activation. Moreover, LCL-161 treatment of lymphoma-bearing mice resulted in apparent disease acceleration concurrent to augmented inflammatory cytokine-release in the same animals. Indiscriminate exposure of lymphoma patients to SMAC mimetics may therefore be detrimental due to both unanticipated prolymphoma effects and increased susceptibility to endotoxic shock.
authors.affiliation: Gene Regulation Laboratory, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia.|Hudson Institute of Medical Research, Clayton, VIC, Australia.|Department of Molecular and Translational Sciences, Monash University, Clayton, VIC, Australia.
authors.forename: A C
authors.initials: AC
authors.lastname: West
authors.affiliation: Gene Regulation Laboratory, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia.
authors.forename: B P
authors.initials: BP
authors.lastname: Martin
authors.affiliation: Department of Microbiology & Immunology, Central Clinical School, Monash University, Clayton, VIC, Australia.
authors.forename: D A
authors.initials: DA
authors.lastname: Andrews
authors.affiliation: Gene Regulation Laboratory, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia.|Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia.
authors.forename: S J
authors.initials: SJ
authors.lastname: Hogg
authors.affiliation: Hudson Institute of Medical Research, Clayton, VIC, Australia.|Centre for Inflammatory Diseases, Monash University, Clayton, VIC, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Banerjee
authors.affiliation: Hudson Institute of Medical Research, Clayton, VIC, Australia.|Alfred Pathology Service, Alfred Health, Prahran, VIC, Australia.|Monash Haematology, Monash Health, Clayton, VIC, Australia.|School of Clinical Sciences, Monash Health, Monash University, Clayton, VIC, Australia.
authors.forename: G
authors.initials: G
authors.lastname: Grigoriadis
authors.affiliation: Gene Regulation Laboratory, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia.|Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia.
authors.forename: R W
authors.initials: RW
authors.lastname: Johnstone
authors.affiliation: Gene Regulation Laboratory, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia.|Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia.|Monash Haematology, Monash Health, Clayton, VIC, Australia.|School of Clinical Sciences, Monash Health, Monash University, Clayton, VIC, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Shortt