title: Pre-clinical evidence of PIM kinase inhibitor activity in BCR-ABL1 unmutated and mutated Philadelphia chromosome-positive (Ph+) leukemias.
abstract: We investigated the efficacy of targeting the PIM kinase pathway in Philadelphia chromosome-positive (Ph+) leukemias. We provide evidence that inhibition of PIM, with the pan-PIM inhibitor SGI-1776, results in suppression of classic PIM effectors and also elements of the mTOR pathway, suggesting interplay between PIM and mTOR signals. Our data demonstrate that PIM inhibition enhances the effects of imatinib mesylate on Ph+ leukemia cells. We also found that PIM inhibition results in suppression of leukemic cell proliferation and induction of apoptosis of Ph+ leukemia cells, including those resistant to imatinib mesylate. Importantly, inhibition of PIM results in enhanced suppression of primary leukemic progenitors from patients with CML. Altogether these findings suggest that pharmacological PIM targeting may provide a unique therapeutic approach for the treatment of Ph+ leukemias.
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.|Division of Hematology-Oncology, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University, Chicago, IL, USA.
authors.forename: Dany A
authors.initials: DA
authors.lastname: Curi
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.|Division of Hematology-Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.|Division of Hematology-Oncology, Department of Medicine, Jesse Brown VA Medical Center, Chicago, IL, USA.
authors.forename: Elspeth M
authors.initials: EM
authors.lastname: Beauchamp
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.|Division of Hematology-Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Gavin T
authors.initials: GT
authors.lastname: Blyth
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.|Division of Hematology-Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Ahmet Dirim
authors.initials: AD
authors.lastname: Arslan
authors.affiliation: Department of Pharmacology, University of Michigan School of Medicine, Ann Arbor, MI, USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Donato
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.|Division of Hematology-Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Giles
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.|Division of Hematology-Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.|Division of Hematology-Oncology, Department of Medicine, Jesse Brown VA Medical Center, Chicago, IL, USA.
authors.forename: Jessica K
authors.initials: JK
authors.lastname: Altman
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.|Division of Hematology-Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.|Division of Hematology-Oncology, Department of Medicine, Jesse Brown VA Medical Center, Chicago, IL, USA.
authors.forename: Leonidas C
authors.initials: LC
authors.lastname: Platanias
mesh_terms: D004305:Dose-Response Relationship, Drug; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D016313:Genes, abl / Q000235:genetics*; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology*; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics* / Q000473:pathology*; D009154:Mutation; D010677:Philadelphia Chromosome; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051562:Proto-Oncogene Proteins c-bcr / Q000235:genetics*; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors; D011724:Pyridazines / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; C545188:SGI 1776; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; C496613:BCR protein, human; D051562:Proto-Oncogene Proteins c-bcr; D051573:Proto-Oncogene Proteins c-pim-1; C406031:proto-oncogene proteins pim
keywords: CML; PIM kinase; mTOR signaling; philadelphia chromosome-positive leukemia