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Cell Press, Cancer Cell, 2(29), p. 145-158

DOI: 10.1016/j.ccell.2016.01.006

Cell Press, Cancer Cell, 3(30), p. 499-500, 2016

DOI: 10.1016/j.ccell.2016.08.009

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

Journal article published in 2016 by Najoua Lalaoui, Kay Hänggi, Gabriela Brumatti, Diep Chau, Nhu-Yn N. Nguyen, Lazaros Vasilikos, Lisanne M. Spilgies, Denise A. Heckmann, Chunyan Ma, Margherita Ghisi, Jessica M. Salmon ORCID, Geoffrey M. Matthews, Elisha de Valle, Donia M. Moujalled, Manoj B. Menon and other authors.
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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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.