title: Antagonism of SET using OP449 enhances the efficacy of tyrosine kinase inhibitors and overcomes drug resistance in myeloid leukemia.
abstract: OBJECTIVE
  The SET oncoprotein, a potent inhibitor of the protein phosphatase 2A (PP2A), is overexpressed in leukemia. We evaluated the efficacy of SET antagonism in chronic myeloid leukemia (CML) and acute myeloid leukemia (AML) cell lines, a murine leukemia model, and primary patient samples using OP449, a specific, cell-penetrating peptide that antagonizes SET's inhibition of PP2A.
  
  
  METHODS
  In vitro cytotoxicity and specificity of OP449 in CML and AML cell lines and primary samples were measured using proliferation, apoptosis, and clonogenic assays. Efficacy of target inhibition by OP449 was evaluated by immunoblotting and PP2A assay. In vivo antitumor efficacy of OP449 was measured in human HL-60 xenografted murine model.
  
  
  RESULTS
  We observed that OP449 inhibited growth of CML cells including those from patients with blastic phase disease and patients harboring highly drug-resistant BCR-ABL1 mutations. Combined treatment with OP449 and ABL1 tyrosine kinase inhibitors was significantly more cytotoxic to K562 cells and primary CD34(+) CML cells. SET protein levels remained unchanged with OP449 treatment, but BCR-ABL1-mediated downstream signaling was significantly inhibited with the degradation of key signaling molecules such as BCR-ABL1, STAT5, and AKT. Similarly, AML cell lines and primary patient samples with various genetic lesions showed inhibition of cell growth after treatment with OP449 alone or in combination with respective kinase inhibitors. Finally, OP449 reduced the tumor burden of mice xenografted with human leukemia cells.
  
  
  CONCLUSIONS
  We demonstrate a novel therapeutic paradigm of SET antagonism using OP449 in combination with tyrosine kinase inhibitors for the treatment of CML and AML.
authors.affiliation: Authors' Affiliations: Knight Cancer Institute; Division of Hematology & Medical Oncology; Departments of Cell and Developmental Biology and Molecular and Medical Genetics, Oregon Health and Science University; Howard Hughes Medical Institute, Portland, Oregon; Oncotide Pharmaceuticals, Research Triangle Park; Duke University Medical Center, Durham, North Carolina; and Division of Oncology, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors.forename: Anupriya
authors.initials: A
authors.lastname: Agarwal
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: MacKenzie
authors.forename: Raffaella
authors.initials: R
authors.lastname: Pippa
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Eide
authors.forename: Jessica
authors.initials: J
authors.lastname: Oddo
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Tyner
authors.forename: Rosalie
authors.initials: R
authors.lastname: Sears
authors.forename: Michael P
authors.initials: MP
authors.lastname: Vitek
authors.forename: María D
authors.initials: MD
authors.lastname: Odero
authors.forename: Dale J
authors.initials: DJ
authors.lastname: Christensen
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Druker
mesh_terms: D000368:Aged; D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004268:DNA-Binding Proteins; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism; D018922:HL-60 Cells; D056488:Histone Chaperones / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D020014:K562 Cells; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D018345:Mice, Knockout; D008875:Middle Aged; D008969:Molecular Sequence Data; D010455:Peptides / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D054648:Protein Phosphatase 2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D004268:DNA-Binding Proteins; D056488:Histone Chaperones; C583613:OP449 peptide; D010455:Peptides; D047428:Protein Kinase Inhibitors; C513473:SET protein, human; D014157:Transcription Factors; D016044:Fusion Proteins, bcr-abl; D054648:Protein Phosphatase 2