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

Najoua Lalaoui, Kay Hanggi, 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 CondonRaffi Gugasyan, Matthias Gaestel, Mark Guthridge, Ricky W Johnstone, Lenka Munoz, Andrew Wei, Paul G Ekert, David L Vaux, W. Wei-Lynn Wong, John Silke

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49 Citations (Scopus)

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. Lalaoui et al. show that inhibition of p38 or its downstream kinase MK2, in contrast to reducing Toll-like receptor-mediated tumor necrosis factor (TNF) production, increases TNF production upon smac-mimetic (SM) treatment and enhances the anti-tumor efficacy of SM.
Original languageEnglish
Pages (from-to)145 - 158
Number of pages14
JournalCancer Cell
Volume29
Issue number2
DOIs
Publication statusPublished - 2016

Cite this

Lalaoui, N., Hanggi, K., Brumatti, G., Chau, D., Nguyen, N-Y. N., Vasilikos, L., Spilgies, L. M., Heckmann, D. A., Ma, C., Ghisi, M., Salmon, J. M., Matthews, G. M., de Valle, E., Moujalled, D. M., Menon, M. B., Spall, S. K., Glaser, S. P., Richmond, J., Lock, R. B., ... Silke, J. (2016). Targeting p38 or MK2 Enhances the Anti-Leukemic Activity of Smac-Mimetics. Cancer Cell, 29(2), 145 - 158. https://doi.org/10.1016/j.ccell.2016.01.006