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

Abstract

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.

Overcoming Resistance: FLT3 Inhibitors Past, Present, Future and the Challenge of Cure

“…Bregante et al identified 2 out of 18 compounds active against FLT3-ITD AML, WS6 and Ispinesib, and combined them with two approved drugs, Ponatinib and Cabozantinib, in in vitro models (AML cell lines and samples) [ 73 ]. WS6 had a similar mechanism and potency to Ponatinib and Cabozantinib.…”

“…The R/R setting still remains an unmet medical need, because of the high relapse rate observed even after HSCT. In the future, new combinations of FLT3i with inhibitors of JAK2, MEK2, HDAC, Menin, AXL and MDM2 or with multitarget agents here reported [ 73 , 74 , 76 , 77 , 78 , 79 , 81 , 82 , 83 , 87 , 91 , 93 , 94 , 95 , 97 ] and immunotherapies, such as checkpoint inhibitors, vaccines, and adoptive T-cell therapies, may decrease the burden of residual disease and reduce the incidence of relapse and refractoriness.…”