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Tumor Engraftment in a Xenograft Mouse Model of Human Mantle Cell Lymphoma
Published on: March 30, 2018
The SMAC mimetic, LCL-161, reduces survival in aggressive MYC-driven lymphoma while promoting susceptibility to
A C West1,2,3, B P Martin1, D A Andrews4
1Gene Regulation Laboratory, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia.
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.
Insights
Second mitochondrial activator of caspase (SMAC) mimetics like LCL-161 unexpectedly accelerated aggressive lymphoma growth in mice. This suggests potential harm from SMAC mimetic therapy in lymphoma patients due to pro-lymphoma effects.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Inhibitor of apoptosis proteins (IAPs) regulate apoptosis and NFκB signaling.
- Second mitochondrial activator of caspase (SMAC) mimetics disengage IAPs and promote apoptosis.
- SMAC mimetics are being evaluated for hematological malignancies.
Purpose of the Study:
- To evaluate the efficacy of LCL-161, a SMAC mimetic, in the Eμ-Myc model of aggressive Burkitt-like lymphoma.
- To investigate the effects of LCL-161 on lymphoma cells and tumor-bearing mice.
Main Methods:
- Treatment of Eμ-Myc lymphoma-bearing mice with LCL-161.
- Assessment of apoptosis induction, IAP degradation, NFκB activation, and cytokine release.
- Monitoring of lymphoma progression and animal survival.
Main Results:
- LCL-161 treatment led to resistance to apoptosis induction in lymphoma cells.
- Despite on-target IAP degradation and NFκB activation, lymphoma growth was accelerated.
- Increased inflammatory cytokine release and susceptibility to endotoxic shock were observed.
Conclusions:
- LCL-161 demonstrated unexpected pro-lymphoma effects in a preclinical model.
- SMAC mimetic therapy may be detrimental in lymphoma patients, causing disease acceleration.
- Caution is advised due to potential adverse effects including increased susceptibility to endotoxic shock.
