title: The Dual MEK/FLT3 Inhibitor E6201 Exerts Cytotoxic Activity against Acute Myeloid Leukemia Cells Harboring Resistance-Conferring FLT3 Mutations.
abstract: Fms-like tyrosine kinase 3 (FLT3) inhibition has elicited encouraging responses in acute myeloid leukemia (AML) therapy. Unfortunately, unless combined with a bone marrow transplant, disease relapse is frequent. In addition to the acquired point mutations in the FLT3 kinase domain that contribute to FLT3 inhibitor resistance, MEK/ERK signaling is persistently activated in AML cells even when FLT3 phosphorylation is continually suppressed. Thus, concomitant targeting of FLT3 and MAPK may potentially exert synergistic activity to counteract the resistance of AML cells to FLT3-targeted therapy. In this study, we investigated the antileukemia activity of a MEK1 and FLT3 dual inhibitor, E6201, in AML cells resistant to FLT3 inhibition. We found that E6201 exerted profound apoptogenic effects on AML cells harboring resistance-conferring FLT3 mutations. This activity appeared to be p53 dependent, and E6201-induced cytotoxicity was retained under hypoxic culture conditions and during coculture with mesenchymal stem cells that mimic the AML microenvironment. Furthermore, E6201 markedly reduced leukemia burden and improved the survival of mice in a human FLT3-mutated AML model. Collectively, our data provide a preclinical basis for the clinical evaluation of E6201 in AML patients harboring FLT3 mutations, including those who relapse following FLT3-targeted monotherapy.
authors.affiliation: Section of Molecular Hematology and Therapy, The University of Texas MD Anderson Cancer Center, Houston Texas. Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston Texas.
authors.forename: Weiguo
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Section of Molecular Hematology and Therapy, The University of Texas MD Anderson Cancer Center, Houston Texas. Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston Texas.
authors.forename: Gautam
authors.initials: G
authors.lastname: Borthakur
authors.affiliation: Section of Molecular Hematology and Therapy, The University of Texas MD Anderson Cancer Center, Houston Texas. Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston Texas.
authors.forename: Chen
authors.initials: C
authors.lastname: Gao
authors.affiliation: Section of Molecular Hematology and Therapy, The University of Texas MD Anderson Cancer Center, Houston Texas. Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston Texas.
authors.forename: Ye
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Section of Molecular Hematology and Therapy, The University of Texas MD Anderson Cancer Center, Houston Texas. Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston Texas.
authors.forename: Hong
authors.initials: H
authors.lastname: Mu
authors.affiliation: Section of Molecular Hematology and Therapy, The University of Texas MD Anderson Cancer Center, Houston Texas. Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston Texas.
authors.forename: Vivian R
authors.initials: VR
authors.lastname: Ruvolo
authors.affiliation: Eisai Inc., Woodcliff Lake, New Jersey.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Nomoto
authors.affiliation: Eisai Inc., Woodcliff Lake, New Jersey.
authors.forename: Nanding
authors.initials: N
authors.lastname: Zhao
authors.affiliation: Section of Molecular Hematology and Therapy, The University of Texas MD Anderson Cancer Center, Houston Texas. Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston Texas.
authors.forename: Marina
authors.initials: M
authors.lastname: Konopleva
authors.affiliation: Section of Molecular Hematology and Therapy, The University of Texas MD Anderson Cancer Center, Houston Texas. Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston Texas. mandreef@mdanderson.org.
authors.forename: Michael
authors.initials: M
authors.lastname: Andreeff
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D005260:Female; D006801:Humans; D007783:Lactones / Q000494:pharmacology*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000235:genetics; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D017354:Point Mutation / Q000187:drug effects* / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors*
chemical_list: C545120:14-(ethylamino)-8,9,16-trihydroxy-3,4-dimethyl-3,4,9,19-tetrahydro-1H-2-benzoxacyclotetradecine-1,7(8H)-dione; D007783:Lactones; D047428:Protein Kinase Inhibitors; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3
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