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

Najoua Lalaoui; Kay Hänggi; Gabriela Brumatti; Diep Chau; Nhu-Y N Nguyen; Lazaros Vasilikos; Lisanne M Spilgies; Denise A Heckmann; Chunyan Ma; Margherita Ghisi; Jessica M Salmon; Geoffrey M Matthews; Elisha de Valle; Donia M Moujalled; Manoj B Menon; Sukhdeep Kaur Spall; Stefan P Glaser; Jennifer Richmond; Richard B Lock; Stephen M Condon; Raffi Gugasyan; Matthias Gaestel; Mark Guthridge; Ricky W Johnstone; Lenka Munoz; Andrew Wei; Paul G Ekert; David L Vaux; W Wei-Lynn Wong; John Silke

doi:10.1016/j.ccell.2016.01.006

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

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

Authors

Najoua Lalaoui¹, Kay Hänggi², Gabriela Brumatti¹, Diep Chau¹, Nhu-Y N Nguyen³, Lazaros Vasilikos², Lisanne M Spilgies², Denise A Heckmann¹, Chunyan Ma¹, Margherita Ghisi⁴, Jessica M Salmon⁴, Geoffrey M Matthews⁴, Elisha de Valle⁵, Donia M Moujalled³, Manoj B Menon⁶, Sukhdeep Kaur Spall¹, Stefan P Glaser¹, Jennifer Richmond⁷, Richard B Lock⁷, Stephen M Condon⁸, Raffi Gugasyan⁵, Matthias Gaestel⁶, Mark Guthridge³, Ricky W Johnstone⁴, Lenka Munoz⁹, Andrew Wei³, Paul G Ekert¹⁰, David L Vaux¹, W Wei-Lynn Wong², John Silke¹¹

Affiliations

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.

PMID: 26859455
DOI: 10.1016/j.ccell.2016.01.006

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / pharmacology
Antineoplastic Agents / therapeutic use*
Apoptosis Regulatory Proteins
Humans
Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
Intracellular Signaling Peptides and Proteins / physiology*
Leukemia / drug therapy*
Mice
Mitochondrial Proteins / physiology*
Molecular Mimicry*
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Tumor Necrosis Factor-alpha / biosynthesis
p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors*

Substances

Antineoplastic Agents
Apoptosis Regulatory Proteins
DIABLO protein, human
Intracellular Signaling Peptides and Proteins
Mitochondrial Proteins
Tumor Necrosis Factor-alpha
MAP-kinase-activated kinase 2
Protein Serine-Threonine Kinases
p38 Mitogen-Activated Protein Kinases