Rational combination of homoharringtonine to selectively target FLT3-ITD acute myeloid leukemia through synthetic lethality.

BACKGROUND

Homoharringtonine (HHT), a natural product used clinically to treat acute myeloid leukemia (AML) in combination with chemotherapy, induced transient remission in 25 % of unclassified AML patients when administered alone. Recent studies showed that HHT could be combined with targeting agents for AML treatment. However, the rationales of these combinations require further exploration to optimize therapeutic efficacy.

PURPOSE: To explore the sensitive subgroup of AML cells to HHT and to evaluate its optimal combinations with FLT3-ITD or Bcl-2 inhibitors based on apoptosis induction.

METHODS

AML cell lines harboring FLT3-ITD mutation and wild-type FLT3 were used to compare the apoptosis induction of HHT alone and in combination with venetoclax or FLT3-ITD inhibitor. siRNA and Western blotting were used to identify the key factors in the apoptosis induction. Xenograft models were used to test the in vivo antileukemia efficacy and toxicity.

RESULTS

FLT3-ITD AML cell lines and primary AML cells exhibited greater sensitivity to HHT-induced apoptosis and in vivo antileukemia effects than FLT3 wild-type cells. HHT induces apoptosis through repressing the antiapoptotic protein Mcl-1 and activating the proapoptotic protein Bax, which is attenuated by Mcl-1 overexpression and Bax knockdown. HHT in combination with Bcl-2 inhibitor venetoclax induce synergistic apoptosis across all cell lines with enhanced toxicity observed in vivo. HHT plus FLT3 inhibitors, including midostaurin, quizartinib, gilteritinib and sorafenib, induce selective synergistic apoptosis in FLT3-ITD AML cells, with the most potent effect observed in the combination of HHT and quizartinib. HHT plus quizartinib significantly prolonged FLT3-ITD AML xenograft survival without causing toxicity.

CONCLUSIONS

FLT3-ITD AML cells represent a responsive subgroup to HHT treatment in vitro and in vivo. The combination of HHT and quizartinib demonstrates optimal efficacy and selectivity against FLT3-ITD AML cells in xenografts, with no observed toxicity.