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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.

Original publication

DOI

10.1016/j.ccell.2016.01.006

Type

Journal article

Journal

Cancer Cell

Publication Date

08/02/2016

Volume

29

Pages

145 - 158

Keywords

Animals, Antineoplastic Agents, Humans, Intracellular Signaling Peptides and Proteins, Leukemia, Mice, Mitochondrial Proteins, Molecular Mimicry, Protein-Serine-Threonine Kinases, Tumor Necrosis Factor-alpha, p38 Mitogen-Activated Protein Kinases