Journal article
Targeting p38 or MK2 Enhances the Anti-Leukemic Activity of Smac-Mimetics
N Lalaoui, K Hänggi, G Brumatti, D Chau, NYN Nguyen, L Vasilikos, LM Spilgies, DA Heckmann, C Ma, M Ghisi, JM Salmon, GM Matthews, E de Valle, DM Moujalled, MB Menon, SK Spall, SP Glaser, J Richmond, RB Lock, SM Condon Show all
Cancer Cell | CELL PRESS | Published : 2016
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, clinica..
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Awarded by Australian Research Council
Funding Acknowledgements
We thank V. Dixit for Ripk3<SUP>-/-</SUP>, H. Korner for Tnfr1<SUP>-/-</SUP>, W. Alexander for Mlkl<SUP>-/-</SUP>, S. Hedrick for Casp8<SUP>fl/fl</SUP>, M. Pasparakis for Mapk14<SUP>fl/fl</SUP> mice, and the Burnet Institute Immuno Monitoring Facility for technical assistance. This work was supported by NHMRC grants (1016647, 461221, 1016701, 1025594, 1046984, 1046010, 1025239, 637367, 1008131, 1081221, 1051235 and 1057905), Cancer Council Victoria grant-in-aid to S.P.G., NHMRC fellowships to J.S. (541901, 1058190) and D.V. (1020136), Association pour la Recherche sur le Cancer (ARC) fellowship to N.L., Peter Muller fellowship to K.H. with additional support from the Australian Cancer Research Fund, Victorian State Government Operational Infrastructure Support, NHMRC IRIISS grant (361646), grant SFB566 from Deutsche Forschungsgemeinschaft (M. Gaestel), and SNSF project grant (310030-138085). S.C. is an employee, and J.S. and D.V. are on the SAB of TetraLogic Pharmaceuticals. A.W. is performing a clinical trial for Tetralogic with birinapant. J.S, D.V., and N.L. are inventors of a patent describing the combination of smac-mimetic plus p38 inhibitor to treat cancer.