Targeting p38 or MK2 Enhances the Anti-Leukemic Activity of Smac-Mimetics.
Lalaoui N., Hänggi K., Brumatti G., Chau D., Nguyen N-YN., 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-L., Silke J.
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.