2. Academic Validation
  3. Dual inhibition of AKT/FLT3-ITD by A674563 overcomes FLT3 ligand-induced drug resistance in FLT3-ITD positive AML

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

  • Oncotarget. 2016 May 17;7(20):29131-42. doi: 10.18632/oncotarget.8675.
Aoli Wang 1 2,  Hong Wu 1 2,  Cheng Chen 1 3,  Chen Hu 1 3,  Ziping Qi 1 3,  Wenchao Wang 1 3,  Kailin Yu 1,  Xiaochuan Liu 1 2,  Fengming Zou 1 3,  Zheng Zhao 1 3,  Jiaxin Wu 1 2,  Juan Liu 1,  Feiyang Liu 1 2,  Li Wang 1 3,  Richard M Stone 4,  Ilene A Galinksy 4,  James D Griffin 4,  Shanchun Zhang 3 5,  Ellen L Weisberg 4,  Jing Liu 1 3,  Qingsong Liu 1 2 3 6
Affiliations

Affiliations

  • 1 High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China.
  • 2 University of Science and Technology of China, Hefei 230036, Anhui, P. R. China.
  • 3 CHMFL-HCMTC Target Therapy Joint Laboratory, Hefei 230031, Anhui, P. R. China.
  • 4 Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
  • 5 Hefei Cosource Medicine Technology Co. Ltd., Hefei 230031, Anhui, P. R. China.
  • 6 Hefei Science Center, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China.
PMID: 27074558 DOI: 10.18632/oncotarget.8675
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.

Keywords

A6745763; AKT; FLT3-ITD; FLT3-ligand; acute myeloid leukemia.

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