Patients with high-risk, relapsed/refractory acute lymphoblastic leukemia (ALL) may be sensitive to treatment with SMAC mimetics, according to researchers.
One SMAC mimetic in particular, birinapant, demonstrated varied activity in samples from ALL patients, but samples from patients with resistant disease were the most sensitive to the drug.
Birinapant also had “marked antileukemic effects” in some mice with ALL.
The researchers found this antileukemic activity was dependent on simultaneous activation of apoptosis and necroptosis.
The team reported these findings in Science Translational Medicine.
“Our research reveals that an alternative cell-death program, necroptosis, can be activated in human ALL cells,” said study author Beat Bornhauser, PhD, of the Children’s Hospital Zurich in Switzerland.
“This enables leukemia cells that barely respond to existing chemotherapeutic drugs to be killed off.”
In vitro and in vivo activity
The researchers tested the efficacy of SMAC mimetics in a set of 51 patient-derived B-cell precursor ALL xenografts, which was enriched for samples from relapsed and drug-resistant disease.
The response to birinapant varied greatly, but samples from high-risk or relapsed patients tended to be highly sensitive to the drug.
The researchers observed similar response profiles with the SMAC mimetic LCL161, although this drug proved less potent than birinapant.
The team also evaluated the antileukemic activity of SMAC mimetics in mouse models of ALL.
Birinapant delayed disease progression and induced complete responses in sensitive ALL cases. LCL161, on the other hand, did not display any in vivo activity.
Determining the mechanism of activity
The researchers used CRISPR-Cas9 to determine how SMAC mimetics fight ALL, and they discovered that the drugs trigger both apoptosis and necroptosis.
If the genes responsible for apoptosis were disabled via genome editing, leukemia cells died due to necroptosis after SMAC mimetics had been administered. If necroptotic genes were disabled, apoptosis led to cell death.
Only the simultaneous deactivation of apoptotic and necroptotic genes resulted in the complete resistance of leukemic cells to SMAC mimetics.
Therefore, the researchers concluded that simultaneous activation of apoptosis and necroptosis is responsible for the strong anti-leukemic effect of SMAC mimetics.
“SMAC mimetics have great potential to eliminate leukemia cells in patients that aren’t sensitive to established chemotherapeutic drugs,” Dr Bornhauser said. “They are effectively a double-edged sword. They kill cells that block apoptosis through necroptosis.”
The researchers are now looking for suitable biomarkers to identify patients who might benefit from treatment with SMAC mimetics in clinical trials.
