Journal article
CLL cells are resistant to smac mimetics because of an inability to form a ripoptosome complex.
C Maas, JM Tromp, J van Laar, R Thijssen, JA Elias, A Malara, A Krippner-Heidenreich, J Silke, MH van Oers, E Eldering
Cell Death Disease | NATURE PUBLISHING GROUP | Published : 2013
Abstract
In the lymph node (LN) environment, chronic lymphocytic leukemia (CLL) cells display increased NF-κB activity compared with peripheral blood CLL cells, which contributes to chemoresistance. Antagonists of cellular inhibitor of apoptosis proteins (cIAPs) can induce apoptosis in various cancer cells in a tumor necrosis factor-α (TNFα)-dependent manner and are in preclinical development. Smac-mimetics promote degradation of cIAP1 and cIAP2, which results in TNFR-mediated apoptosis via formation of a ripoptosome complex, comprising RIPK1, Fas-associated protein with death domain, FLICE-like inhibitory protein and caspase-8. CD40 stimulation of CLL cells in vitro is used as a model to mimic the L..
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Awarded by National Health and Medical Research Council
Funding Acknowledgements
We are grateful to Dr. D Lecis and Dr. D Delia (Department of Experimental Oncology, Fondazione IRCCS Instituto Nazionale Tumori, Milano, Italy) for providing SM83. This research was funded by the Dutch Cancer Society (grant UVA 2007-3856-JMT, JAE, EE and MHJvO) and the Stichting Hematologisch Onderzoek (SHO) (CM and JvL). JS is a member of the Scientific Advisory Board of TetraLogic Pharmaceuticals and is supported by an NHMRC Fellowship 541901.