Targeting p38 or MK2 enhances the anti-leukemic activity of smac-mimetics
- Author(s)
- Lalaoui, N; Hanggi, K; Brumatti, G; Chau, D; Nguyen, NY; Vasilikos, L; Spilgies, LM; Heckmann, DA; Ma, C; Ghisi, M; Salmon, JM; Matthews, GM; de Valle, E; Moujalled, DM; Menon, MB; Spall, SK; Glaser, SP; Richmond, J; Lock, RB; Condon, SM; Gugasyan, R; Gaestel, M; Guthridge, M; Johnstone, RW; Munoz, L; Wei, A; Ekert, PG; Vaux, DL; Wong, WW; Silke, J;
- Details
- Publication Year 2016-02-08,Volume 29,Issue #2,Page 145-58
- Journal Title
- Cancer Cell
- Publication Type
- Journal Article
- 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.
- Publisher
- Cell Press
- Research Division(s)
- Cell Signalling And Cell Death; Cancer And Haematology; Systems Biology And Personalised Medicine
- PubMed ID
- 26859455
- Publisher's Version
- https://doi.org/10.1016/j.ccell.2016.01.006
- NHMRC Grants
- NHMRC/1020136, NHMRC/541901, NHMRC/1058190, NHMRC/1016647, NHMRC/461221, NHMRC/1016701, NHMRC/1025594, NHMRC/1046984, NHMRC/1046010, NHMRC/1025239, NHMRC/637367, NHMRC/1008131, NHMRC/1081221, NHMRC/1051235, NHMRC/1057905,
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2016-03-14 03:05:30
Last Modified: 2016-03-14 03:40:26