Targeting p38 or MK2 Enhances the Anti-Leukemic Activity of Smac-Mimetics Academic Article uri icon

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.

authors

  • Lalaoui, N
  • Hänggi, K
  • Brumatti, G
  • Chau, D
  • Nguyen, NYN
  • 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, WWL
  • Silke, J

publication date

  • 2016