Dual inhibition of AKT/FLT3-ITD by A674563 overcomes FLT3 ligand-induced drug resistance in FLT3-ITD positive AML
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Aoli Wang1,2,*, Hong Wu1,2,*, Cheng Chen1,3,*, Chen Hu1,3,*, Ziping Qi1,3,*, Wenchao Wang1,3, Kailin Yu1, Xiaochuan Liu1,2, Fengming Zou1,3, Zheng Zhao1,3, Jiaxin Wu1,2, Juan Liu1, Feiyang Liu1,2, Li Wang1,3, Richard M. Stone4, Ilene A. Galinksy4, James D. Griffin4, Shanchun Zhang3,5, Ellen L. Weisberg4, Jing Liu1,3, Qingsong Liu1,2,3,6
1High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China
2University of Science and Technology of China, Hefei 230036, Anhui, P. R. China
3CHMFL-HCMTC Target Therapy Joint Laboratory, Hefei 230031, Anhui, P. R. China
4Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA
5Hefei Cosource Medicine Technology Co. Ltd., Hefei 230031, Anhui, P. R. China
6Hefei Science Center, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China
*These authors contributed equally to this work
Ellen L. Weisberg, email: [email protected]
Jing Liu, email: [email protected]
Qingsong Liu, email: [email protected]
Keywords: acute myeloid leukemia, FLT3-ITD, AKT, A6745763, FLT3-ligand
Received: December 07, 2015 Accepted: March 28, 2016 Published: April 11, 2016
The FLT3-ITD mutation is one of the most prevalent oncogenic mutations in AML. Several FLT3 kinase inhibitors have shown impressive activity in clinical evaluation, however clinical responses are usually transient and clinical effects are rapidly lost due to drug resistance. One of the resistance mechanisms in the AML refractory patients involves FLT3-ligand induced reactivation of AKT and/or ERK signaling via FLT3 wt kinase. Via a screen of numerous AKT kinase inhibitors, we identified the well-established orally available AKT inhibitor, A674563, as a dual suppressor of AKT and FLT3-ITD. A674563 suppressed FLT3-ITD positive AML both in vitro and in vivo. More importantly, compared to other FLT3 inhibitors, A674563 is able to overcome FLT3 ligand-induced drug resistance through simultaneous inhibition of FLT3-ITD- and AKT-mediated signaling. Our findings suggest that A674563 might be a potential drug candidate for overcoming FLT3 ligand-mediated drug resistance in FLT3-ITD positive AML.
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