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Cancer Cell. 2016 Feb 8;29(2):145-58. doi: 10.1016/j.ccell.2016.01.006.

Targeting p38 or MK2 Enhances the Anti-Leukemic Activity of Smac-Mimetics.

Author information

1
Cell Signaling & Cell Death and Cancer & Hematology Divisions, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3050, Australia.
2
Institute of Experimental Immunology, University of Zürich, Zürich 8057, Switzerland.
3
Department of Clinical Hematology, The Alfred Hospital and Monash University, Melbourne, VIC 3004, Australia; Australian Centre for Blood Diseases, Monash University, Melbourne, VIC 3004, Australia.
4
Gene Regulation Laboratory, Cancer Therapeutics Program, Peter MacCallum Cancer Centre, East Melbourne, VIC 3002, Australia; The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC 3050, Australia.
5
Immunomonitoring Facility and Centre for Biomedical Research, The Burnet Institute, Melbourne, VIC 3004, Australia; Department of Immunology, Central Clinical School, Monash University, Melbourne, VIC 3181, Australia.
6
Institute of Physiological Chemistry, Hannover Medical School, Carl-Neuberg-Street 1, 30625 Hannover, Germany.
7
Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW, Randwick, NSW 2031, Australia.
8
TetraLogic Pharmaceuticals Corporation, 343 Phoenixville Pike, Malvern, PA 19355, USA.
9
Department of Pathology, School of Medical Sciences, University of Sydney, Sydney, NSW 2006, Australia.
10
Cell Signaling & Cell Death and Cancer & Hematology Divisions, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Pediatrics, University of Melbourne, Parkville, VIC 3050, Australia; Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, VIC 3052, Australia.
11
Cell Signaling & Cell Death and Cancer & Hematology Divisions, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3050, Australia. Electronic address: silke@wehi.edu.au.

Abstract

Birinapant is a smac-mimetic (SM) in clinical trials for treating cancer. SM antagonize inhibitor of apoptosis (IAP) proteins and simultaneously induce tumor necrosis factor (TNF) secretion to render cancers sensitive to TNF-induced killing. To enhance SM efficacy, we screened kinase inhibitors for their ability to increase TNF production of SM-treated cells. We showed that p38 inhibitors increased TNF induced by SM. Unexpectedly, even though p38 is required for Toll-like receptors to induce TNF, loss of p38 or its downstream kinase MK2 increased induction of TNF by SM. Hence, we show that the p38/MK2 axis can inhibit or promote TNF production, depending on the stimulus. Importantly, clinical p38 inhibitors overcame resistance of primary acute myeloid leukemia to birinapant.

PMID:
26859455
DOI:
10.1016/j.ccell.2016.01.006
[Indexed for MEDLINE]
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