Sir Peter MacCallum Department of Oncology - Research Publications

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Author: Johnstone, Ricky × Author: Hogg, Simon × Start date: 2015 × End date: 2019 ×

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    CDK9 inhibition by dinaciclib potently suppresses Mcl-1 to induce durable apoptotic responses in aggressive MYC-driven B-cell lymphoma in vivo
    Gregory, GP ; Hogg, SJ ; Kats, LM ; Vidacs, E ; Baker, AJ ; Gilan, O ; Lefebure, M ; Martin, BP ; Dawson, MA ; Johnstone, RW ; Shortt, J (NATURE PUBLISHING GROUP, 2015-06)
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    The SMAC mimetic, LCL-161, reduces survival in aggressive MYC-driven lymphoma while promoting susceptibility to endotoxic shock
    West, AC ; Martin, BP ; Andrews, DA ; Hogg, SJ ; Banerjee, A ; Grigoriadis, G ; Johnstone, RW ; Shortt, J (NATURE PUBLISHING GROUP, 2016-04)
    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.