title: Pim kinase inhibition sensitizes FLT3-ITD acute myeloid leukemia cells to topoisomerase 2 inhibitors through increased DNA damage and oxidative stress.
abstract: Internal tandem duplication of fms-like tyrosine kinase-3 (FLT3-ITD) is frequent (30 percent) in acute myeloid leukemia (AML), and is associated with short disease-free survival following chemotherapy. The serine threonine kinase Pim-1 is a pro-survival oncogene transcriptionally upregulated by FLT3-ITD that also promotes its signaling in a positive feedback loop. Thus inhibiting Pim-1 represents an attractive approach in targeting FLT3-ITD cells. Indeed, co-treatment with the pan-Pim kinase inhibitor AZD1208 or expression of a kinase-dead Pim-1 mutant sensitized FLT3-ITD cell lines to apoptosis triggered by chemotherapy drugs including the topoisomerase 2 inhibitors daunorubicin, etoposide and mitoxantrone, but not the nucleoside analog cytarabine. AZD1208 sensitized primary AML cells with FLT3-ITD to topoisomerase 2 inhibitors, but did not sensitize AML cells with wild-type FLT3 or remission bone marrow cells, supporting a favorable therapeutic index. Mechanistically, the enhanced apoptosis observed with AZD1208 and topoisomerase 2 inhibitor combination treatment was associated with increased DNA double-strand breaks and increased levels of reactive oxygen species (ROS), and co-treatment with the ROS scavenger N-acetyl cysteine rescued FLT3-ITD cells from AZD1208 sensitization to topoisomerase 2 inhibitors. Our data support testing of Pim kinase inhibitors with topoisomerase 2 inhibitors, but not with cytarabine, to improve treatment outcomes in AML with FLT3-ITD.
authors.affiliation: University of Maryland Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.|Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Kshama A
authors.initials: KA
authors.lastname: Doshi
authors.affiliation: University of Maryland Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.|Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Rossana
authors.initials: R
authors.lastname: Trotta
authors.affiliation: University of Maryland Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.|Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Karthika
authors.initials: K
authors.lastname: Natarajan
authors.affiliation: University of Maryland Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.|Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Feyruz V
authors.initials: FV
authors.lastname: Rassool
authors.affiliation: Oncology iMED, AstraZeneca, Waltham, MA, USA.
authors.forename: Adriana E
authors.initials: AE
authors.lastname: Tron
authors.affiliation: Oncology iMED, AstraZeneca, Waltham, MA, USA.
authors.forename: Dennis
authors.initials: D
authors.lastname: Huszar
authors.affiliation: University of Maryland Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.|Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Danilo
authors.initials: D
authors.lastname: Perrotti
authors.affiliation: University of Maryland Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.|Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.|Veterans Affairs Medical Center, Baltimore, MD, USA.
authors.forename: Maria R
authors.initials: MR
authors.lastname: Baer
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000494:pharmacology; D003561:Cytarabine / Q000494:pharmacology; D004249:DNA Damage; D004357:Drug Synergism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D018384:Oxidative Stress / Q000187:drug effects*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D053778:Thiazolidines / Q000008:administration & dosage / Q000494:pharmacology; D059005:Topoisomerase II Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D051941:fms-Like Tyrosine Kinase 3 / Q000378:metabolism*
chemical_list: C587575:AZD1208; D001713:Biphenyl Compounds; D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; D053778:Thiazolidines; D059005:Topoisomerase II Inhibitors; D003561:Cytarabine; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; C496634:PIM1 protein, human; D051573:Proto-Oncogene Proteins c-pim-1
keywords: FLT3-ITD; Pim kinase; acute myeloid leukemia; chemotherapy; reactive oxygen species