title: Dual inhibition of AKT/FLT3-ITD by A674563 overcomes FLT3 ligand-induced drug resistance in FLT3-ITD positive AML.
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.
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China.|University of Science and Technology of China, Hefei 230036, Anhui, P. R. China.
authors.forename: Aoli
authors.initials: A
authors.lastname: Wang
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China.|University of Science and Technology of China, Hefei 230036, Anhui, P. R. China.
authors.forename: Hong
authors.initials: H
authors.lastname: Wu
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China.|CHMFL-HCMTC Target Therapy Joint Laboratory, Hefei 230031, Anhui, P. R. China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Chen
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China.|CHMFL-HCMTC Target Therapy Joint Laboratory, Hefei 230031, Anhui, P. R. China.
authors.forename: Chen
authors.initials: C
authors.lastname: Hu
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China.|CHMFL-HCMTC Target Therapy Joint Laboratory, Hefei 230031, Anhui, P. R. China.
authors.forename: Ziping
authors.initials: Z
authors.lastname: Qi
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China.|CHMFL-HCMTC Target Therapy Joint Laboratory, Hefei 230031, Anhui, P. R. China.
authors.forename: Wenchao
authors.initials: W
authors.lastname: Wang
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China.
authors.forename: Kailin
authors.initials: K
authors.lastname: Yu
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China.|University of Science and Technology of China, Hefei 230036, Anhui, P. R. China.
authors.forename: Xiaochuan
authors.initials: X
authors.lastname: Liu
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China.|CHMFL-HCMTC Target Therapy Joint Laboratory, Hefei 230031, Anhui, P. R. China.
authors.forename: Fengming
authors.initials: F
authors.lastname: Zou
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China.|CHMFL-HCMTC Target Therapy Joint Laboratory, Hefei 230031, Anhui, P. R. China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China.|University of Science and Technology of China, Hefei 230036, Anhui, P. R. China.
authors.forename: Jiaxin
authors.initials: J
authors.lastname: Wu
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China.
authors.forename: Juan
authors.initials: J
authors.lastname: Liu
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China.|University of Science and Technology of China, Hefei 230036, Anhui, P. R. China.
authors.forename: Feiyang
authors.initials: F
authors.lastname: Liu
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China.|CHMFL-HCMTC Target Therapy Joint Laboratory, Hefei 230031, Anhui, P. R. China.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Stone
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Ilene A
authors.initials: IA
authors.lastname: Galinksy
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: James D
authors.initials: JD
authors.lastname: Griffin
authors.affiliation: CHMFL-HCMTC Target Therapy Joint Laboratory, Hefei 230031, Anhui, P. R. China.|Hefei Cosource Medicine Technology Co. Ltd., Hefei 230031, Anhui, P. R. China.
authors.forename: Shanchun
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Ellen L
authors.initials: EL
authors.lastname: Weisberg
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China.|CHMFL-HCMTC Target Therapy Joint Laboratory, Hefei 230031, Anhui, P. R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China.|University of Science and Technology of China, Hefei 230036, Anhui, P. R. China.|CHMFL-HCMTC Target Therapy Joint Laboratory, Hefei 230031, Anhui, P. R. China.|Hefei Science Center, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China.
authors.forename: Qingsong
authors.initials: Q
authors.lastname: Liu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; D051057:Proto-Oncogene Proteins c-akt
keywords: A6745763; AKT; FLT3-ITD; FLT3-ligand; acute myeloid leukemia