title: A potential therapeutic target for FLT3-ITD AML: PIM1 kinase.
abstract: Patients with acute myeloid leukemia (AML) and a FLT3 internal tandem duplication (ITD) mutation have a poor prognosis, and FLT3 inhibitors are now under clinical investigation. PIM1, a serine/threonine kinase, is up-regulated in FLT3-ITD AML and may be involved in FLT3-mediated leukemogenesis. We employed a PIM1 inhibitor, AR00459339 (Array Biopharma Inc.), to investigate the effect of PIM1 inhibition in FLT3-mutant AML. Like FLT3 inhibitors, AR00459339 was preferentially cytotoxic to FLT3-ITD cells, as demonstrated in the MV4-11, Molm-14, and TF/ITD cell lines, as well as 12 FLT3-ITD primary samples. Unlike FLT3 inhibitors, AR00459339 did not suppress phosphorylation of FLT3, but did promote the de-phosphorylation of downstream FLT3 targets, STAT5, AKT, and BAD. Combining AR00459339 with a FLT3 inhibitor resulted in additive to mildly synergistic cytotoxic effects. AR00459339 was cytotoxic to FLT3-ITD samples from patients with secondary resistance to FLT3 inhibitors, suggesting a novel benefit to combining these agents. We conclude that PIM1 appears to be closely associated with FLT3 signaling, and that inhibition of PIM1 may hold therapeutic promise, either as monotherapy, or by overcoming resistance to FLT3 inhibitors.
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA. afathi@partners.org
authors.forename: Amir T
authors.initials: AT
authors.lastname: Fathi
authors.forename: Omotayo
authors.initials: O
authors.lastname: Arowojolu
authors.forename: Ian
authors.initials: I
authors.lastname: Swinnen
authors.forename: Takashi
authors.initials: T
authors.lastname: Sato
authors.forename: Trivikram
authors.initials: T
authors.lastname: Rajkhowa
authors.forename: Donald
authors.initials: D
authors.lastname: Small
authors.forename: Fredrik
authors.initials: F
authors.lastname: Marmsater
authors.forename: John E
authors.initials: JE
authors.lastname: Robinson
authors.forename: Stefan David
authors.initials: SD
authors.lastname: Gross
authors.forename: Matthew
authors.initials: M
authors.lastname: Martinson
authors.forename: Shelley
authors.initials: S
authors.lastname: Allen
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Kallan
authors.forename: Mark
authors.initials: M
authors.lastname: Levis
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001853:Bone Marrow / Q000187:drug effects; D003114:Colony-Forming Units Assay; D004359:Drug Therapy, Combination; D006801:Humans; D047468:Immunoprecipitation; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction; D020080:Tandem Repeat Sequences / Q000235:genetics; D014407:Tumor Cells, Cultured; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; C496634:PIM1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D051573:Proto-Oncogene Proteins c-pim-1