Wu-5,a Novel USP10 Inhibitor,Synergistically Enhances Crenolanib-induced Cell Death In FLT3-ITD-positive AML Cells Via Inhibiting AMPK And FLT3 Pathways

The kinase FLT3 internal tandem duplication(FLT3-ITD)is related to poor clinical outcomes of acute myeloid leukemia(AML).The introduction of FLT3 inhibitor has provided novel weapons for the treatment of FLT-ITD positive AML.However,single-agent treatment always shows drug resistance and transit clinical response.Finding novel strategy to overcome drug resistance and enhance the efficacy of FLT3 inhibitors is required.Here we show that Wu-5selectively induces apoptosis in FLT3 inhibitor-sensitive and-resistant FLT3-ITD positive AML cells.Wu-5 treatment results in the proteasome-mediated degradation of FLT3-ITD.We further demonstrated that Wu-5 directly interacts with and inactivation USP10,the deubiquitinase for FLT3-ITD,in cells.Combined treatment Wu-5 with crenolanib causes synergistic cell death in FLT3-ITD positive cells via reduction of both FLT3-ITD and AMPKα proteins.Interestingly,overexpression of USP10 abrogates the Wu-5-induced FLT3-ITD degradation,cell death and the enhancing effect of Wu-5 on FLT3 inhibitor.In summary,we demonstrated that Wu-5,a novel USP10 inhibitor,could overcome FLT3 inhibitor resistance and synergistically enhance the anti-AML effect of crenolanib through targeting FLT3 and AMPKα pathway.