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Dual inhibition of AKT/FLT3-ITD by A674563 overcomes FLT3 ligand-induced drug resistance in FLT3-ITD positive AML
- Source :
- Wang, A., H. Wu, C. Chen, C. Hu, Z. Qi, W. Wang, K. Yu, et al. 2016. “Dual inhibition of AKT/FLT3-ITD by A674563 overcomes FLT3 ligand-induced drug resistance in FLT3-ITD positive AML.” Oncotarget 7 (20): 29131-29142. doi:10.18632/oncotarget.8675. http://dx.doi.org/10.18632/oncotarget.8675.
- Publication Year :
- 2016
- Publisher :
- Impact Journals LLC, 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.
- Subjects :
- acute myeloid leukemia
FLT3-ITD
AKT
A6745763
FLT3-ligand
Subjects
Details
- Language :
- English
- ISSN :
- 19492553
- Database :
- Digital Access to Scholarship at Harvard (DASH)
- Journal :
- Wang, A., H. Wu, C. Chen, C. Hu, Z. Qi, W. Wang, K. Yu, et al. 2016. “Dual inhibition of AKT/FLT3-ITD by A674563 overcomes FLT3 ligand-induced drug resistance in FLT3-ITD positive AML.” Oncotarget 7 (20): 29131-29142. doi:10.18632/oncotarget.8675. http://dx.doi.org/10.18632/oncotarget.8675.
- Publication Type :
- Academic Journal
- Accession number :
- edshld.1.29408298
- Document Type :
- Journal Article
- Full Text :
- https://doi.org/10.18632/oncotarget.8675