Oncotarget

Research Papers:

Dual inhibition of AKT/FLT3-ITD by A674563 overcomes FLT3 ligand-induced drug resistance in FLT3-ITD positive AML

Aoli Wang, Hong Wu, Cheng Chen, Chen Hu, Ziping Qi, Wenchao Wang, Kailin Yu, Xiaochuan Liu, Fengming Zou, Zheng Zhao, Jiaxin Wu, Juan Liu, Feiyang Liu, Li Wang, Richard M. Stone, Ilene A. Galinksy, James D. Griffin, Shanchun Zhang, Ellen L. Weisberg, Jing Liu and Qingsong Liu _

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Oncotarget. 2016; 7:29131-29142. https://doi.org/10.18632/oncotarget.8675

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Abstract

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

Correspondence to:

Ellen L. Weisberg, email: Ellen_weisberg@dfci.harvard.edu

Jing Liu, email: jingliu@hmfl.ac.cn

Qingsong Liu, email: qsliu97@hmfl.ac.cn

Keywords: acute myeloid leukemia, FLT3-ITD, AKT, A6745763, FLT3-ligand

Received: December 07, 2015     Accepted: March 28, 2016     Published: April 11, 2016

ABSTRACT

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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