Larrue C, (2016) Blood, Link to abstract)
FLT3-ITD positive AML is a subset of AML with poor prognosis. The authors examined the effect of bortezomib, a proteasome-inhibitor, on FLT3-ITD positive AML cells in vitro. The authors found that FLT3-ITD positive cells were more sensitive to bortezomib than wild-type cells. This effect was stronger, the higher the FLT3-ITD expression was. The mechanisms identified leading to this sensitivity were through cytotoxic autophagy. FLT3-ITD molecules were identified within autophagosomes which led to MAPK/ ERK, PI3K/ AKT, and STAT5 pathway inhibition and ultimately to cell death. Bortezomib treatment led to sensitivity to a second-generation tyrosine kinase inhibitor with high FLT3 selectivity (quizartinib) in cells that were found to be resistant prior to bortezomib application. Finally, in xenograft mice models, bortezomib led to induction of autophagy and improved survival.
* The results of this study provide a theoretical basis to consider treatment with bortezomib and a tyrosine-kinase inhibitor with high FLT3 selectivity in patients with FLT3-ITD positive AML.