Efficacy and Synergy of Small Molecule Inhibitors Targeting FLT3-ITD+ Acute Myeloid Leukemia

Cancers

Elvin D. de Araujo¹  Peter Valent²  Lina Degenfeld-Schonburg²  Emir Hadzijusufovic²  Javier Bregante³  Daniel Pölöske³  Garazi Monzó Contreras³  Anna Orlova³  Anna Schönbichler³  Richard Moriggl³ 

[1] Department of Chemical and Physical Sciences, University of Toronto Mississauga, Mississauga, ON L5L1C6, Canada;Department of Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, 1090 Vienna, Austria;Institute of Animal Breeding and Genetics, University of Veterinary Medicine, 1210 Vienna, Austria;

关键词: acute myeloid leukemia;    tyrosine kinase inhibitor;    FMS-like tyrosine kinase 3;    targeted therapy;    ponatinib;    cabozantinib;   

DOI  :  10.3390/cancers13246181

来源: DOAJ

【 摘 要 】

Constitutive activation of FLT3 by ITD mutations is one of the most common genetic aberrations in AML, present in ~1/3 of cases. Patients harboring FLT3-ITD display worse clinical outcomes. The integration and advancement of FLT3 TKI in AML treatment provided significant therapeutic improvement. However, due to the emergence of resistance mechanisms, FLT3-ITD⁺ AML remains a clinical challenge. We performed an unbiased drug screen to identify 18 compounds as particularly efficacious against FLT3-ITD⁺ AML. Among these, we characterized two investigational compounds, WS6 and ispinesib, and two approved drugs, ponatinib and cabozantinib, in depth. We found that WS6, although not yet investigated in oncology, shows a similar mechanism and potency as ponatinib and cabozantinib. Interestingly, ispinesib and cabozantinib prevent activation of AXL, a key driver and mechanism of drug resistance in FLT3-ITD⁺ AML patients. We further investigated synergies between the selected compounds and found that combination treatment with ispinesib and cabozantinib or ponatinib shows high synergy in FLT3-ITD⁺ AML cell lines and patient samples. Together, we suggest WS6, ispinesib, ponatinib and cabozantinib as novel options for targeting FLT3-ITD⁺ AML. Whether combinatorial tyrosine kinase and kinesin spindle blockade is effective in eradicating neoplastic (stem) cells in FLT3-ITD⁺ AML remains to be determined in clinical trials.

【 授权许可】

Unknown