The caspase-8 inhibitor emricasan combines with the SMAC mimetic birinapant to induce necroptosis and treat acute myeloid leukemia Academic Article uri icon

abstract

  • Resistance to chemotherapy is a major problem in cancer treatment, and it is frequently associated with failure of tumor cells to undergo apoptosis. Birinapant, a clinical SMAC mimetic, had been designed to mimic the interaction between inhibitor of apoptosis proteins (IAPs) and SMAC/Diablo, thereby relieving IAP-mediated caspase inhibition and promoting apoptosis of cancer cells. We show that acute myeloid leukemia (AML) cells are sensitive to birinapant-induced death and that the clinical caspase inhibitor emricasan/IDN-6556 augments, rather than prevents, killing by birinapant. Deletion of caspase-8 sensitized AML to birinapant, whereas combined loss of caspase-8 and the necroptosis effector MLKL (mixed lineage kinase domain-like) prevented birinapant/IDN-6556-induced death, showing that inhibition of caspase-8 sensitizes AML cells to birinapant-induced necroptosis. However, loss of MLKL alone did not prevent a caspase-dependent birinapant/IDN-6556-induced death, implying that AML will be less likely to acquire resistance to this drug combination. A therapeutic breakthrough in AML has eluded researchers for decades. Demonstrated antileukemic efficacy and safety of the birinapant/emricasan combination in vivo suggest that induction of necroptosis warrants clinical investigation as a therapeutic opportunity in AML.

authors

  • Brumatti, G
  • Ma, C
  • Lalaoui, N
  • Nguyen, NY
  • Navarro, M
  • Tanzer, MC
  • Richmond, J
  • Ghisi, M
  • Salmon, JM
  • Silke, N
  • Pomilio, G
  • Glaser, SP
  • De Valle, E
  • Gugasyan, R
  • Gurthridge, MA
  • Condon, SM
  • Johnstone, RW
  • Lock, R
  • Salvesen, G
  • Wei, A
  • Vaux, DL
  • Ekert, PG
  • Silke, J

publication date

  • May 18, 2016