The SMAC mimetic, LCL-161, reduces survival in aggressive MYC-driven lymphoma while promoting susceptibility to endotoxic shock
AC West, BP Martin, DA Andrews, SJ Hogg, A Banerjee, G Grigoriadis, RW Johnstone, J Shortt
ONCOGENESIS | NATURE PUBLISHING GROUP | Published : 2016
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 ..View full abstract
ACW was supported by the Cancer Council of Victoria (CCV). SJH is funded by the Leukaemia Foundation of Australia (LFA). JS is supported by funding from the CCV, LFA, Eva & Les Erdi/Snowdome Foundation and Victorian Cancer Agency (VCA). RWJ is a Senior Principal Research Fellow of the National Health & Medical Research Council of Australia (NHMRC) and is supported by NHMRC Program and Project Grants, the CCV and VCA. GG is a VCA Clinical Research Fellow. DAA is supported by an NHMRC Career Development Fellowship.