title: Identification of novel therapeutic targets in acute leukemias with NRAS mutations using a pharmacologic approach.
abstract: Oncogenic forms of NRAS are frequently associated with hematologic malignancies and other cancers, making them important therapeutic targets. Inhibition of individual downstream effector molecules (eg, RAF kinase) have been complicated by the rapid development of resistance or activation of bypass pathways. For the purpose of identifying novel targets in NRAS-transformed cells, we performed a chemical screen using mutant NRAS transformed Ba/F3 cells to identify compounds with selective cytotoxicity. One of the compounds identified, GNF-7, potently and selectively inhibited NRAS-dependent cells in preclinical models of acute myelogenous leukemia and acute lymphoblastic leukemia. Mechanistic analysis revealed that its effects were mediated in part through combined inhibition of ACK1/AKT and of mitogen-activated protein kinase kinase kinase kinase 2 (germinal center kinase). Similar to genetic synthetic lethal approaches, these results suggest that small molecule screens can be used to identity novel therapeutic targets in cells addicted to RAS oncogenes.
authors.affiliation: Department of Medical Oncology and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nonami
authors.affiliation: Department of Medical Oncology and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Martin
authors.initials: M
authors.lastname: Sattler
authors.affiliation: Department of Medical Oncology and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Ellen
authors.initials: E
authors.lastname: Weisberg
authors.affiliation: Department of Medicine and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA;
authors.forename: Qingsong
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Medicine and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA;
authors.forename: Jianming
authors.initials: J
authors.lastname: Zhang
authors.affiliation: ActivX Biosciences, Inc., La Jolla, CA;
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Patricelli
authors.affiliation: Lurie Family Imaging Center, Dana-Farber Cancer Institute, MA;
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Christie
authors.affiliation: Lurie Family Imaging Center, Dana-Farber Cancer Institute, MA;
authors.forename: Amy M
authors.initials: AM
authors.lastname: Saur
authors.affiliation: Lurie Family Imaging Center, Dana-Farber Cancer Institute, MA;
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Kohl
authors.affiliation: Lurie Family Imaging Center, Dana-Farber Cancer Institute, MA;
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Kung
authors.affiliation: Chemical Kinomics Research Center, Korea Institute of Science and Technology, Seoul, Korea; and.
authors.forename: Hojong
authors.initials: H
authors.lastname: Yoon
authors.affiliation: Chemical Kinomics Research Center, Korea Institute of Science and Technology, Seoul, Korea; and KU-KIST Graduate School of Converging Science and Technology, Seongbuk-gu, Seoul, Korea.
authors.forename: Taebo
authors.initials: T
authors.lastname: Sim
authors.affiliation: Department of Medicine and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA;
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
authors.affiliation: Department of Medical Oncology and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: James D
authors.initials: JD
authors.lastname: Griffin
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004354:Drug Screening Assays, Antitumor; D020558:GTP Phosphohydrolases / Q000235:genetics* / Q000378:metabolism; D000081410:Germinal Center Kinases; D006801:Humans; D007938:Leukemia / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011744:Pyrimidinones / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D000081410:Germinal Center Kinases; D008565:Membrane Proteins; C551935:N-(4-methyl-3-(1-methyl-7-(6-methylpyridin-3-ylamino)-2-oxo-1,2-dihydropyrimido(4,5-d)pyrimidin-3(4H)-yl)phenyl)-3-(trifluoromethyl)benzamide; D047428:Protein Kinase Inhibitors; D011744:Pyrimidinones; D054852:Small Molecule Libraries; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human
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