Abstract
Simple SummaryFLT3-ITD mutations belong to the most frequent yet most detrimental genetic alterations in AML. Next-generation FLT3 inhibitors are potent therapeutics and often effective in AML patients carrying the FLT3-ITD driver kinase. However, AML cells are particularly quick in acquiring resistance to FLT3 kinase blockers. We aimed to identify novel therapeutic options for FLT3-ITD+ AML, to investigate possible emerging resistance mechanisms to FLT3 inhibitors and to explore alternative targeting strategies. We applied a kinase-focused drug screen to find alternative therapeutics. We identified ispinesib, a kinesin spindle blocker, and kinase blockers WS6, ponatinib and cabozantinib, as very efficacious agents against FLT3-ITD+ AML cells. Importantly, we identify the combination of cabozantinib and ispinesib as particularly potent against FLT3-ITD+ AML. We suggest that a combinatorial treatment with these drugs could overcome resistance mechanisms and kill FLT3-ITD+ AML blasts.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.
Highlights
Acute myeloid leukemia (AML) is a hematopoietic malignancy defined by an abnormal proliferation and accumulation of poorly differentiated myeloid progenitor cells [1].AML constitutes the most common acute leukemia in adults, but despite innovative therapeutic strategies, largely based on targeted tyrosine kinase inhibitors (TKI) or chemotherapeutic intervention, ~70% of patients >65 of age still succumb to the disease within one year after diagnosis [2,3]
These results indicate that the drug screening carried out in two AML cell lines yielded a dataset of potent small molecule inhibitors against AML
We studied the combination of ispinesib with current standard of care drugs for FLT3-ITD+ AML, including broad-spectrum chemotherapeutic drugs, approved FLT3 inhibitors and the BCL2 family member blocker venetoclax
Summary
AML constitutes the most common acute leukemia in adults, but despite innovative therapeutic strategies, largely based on targeted tyrosine kinase inhibitors (TKI) or chemotherapeutic intervention, ~70% of patients >65 of age still succumb to the disease within one year after diagnosis [2,3]. A reason for this poor prognosis is genetic heterogeneity, clonal evolution of cancer cells and recurrent mutations that lead to vulnerable tyrosine kinase signaling cascades, which characterize AML [1]. This leads to the lack of novel targeted therapeutic for these patients. FLT3 serves as a growth factor receptor displaying intrinsic kinase activity and it is normally expressed by bone marrow stromal cells where it promotes cell survival and proliferation via signaling pathways such as phosphatidylinositol-3 kinase (PI3K)-AKT-mTOR activation, RAS-RAFMAPK cascade triggering and the signal transducer and activator of transcription 5 (STAT5)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
