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: Atsushi Nonami, Martin Sattler, Ellen Weisberg, Qingsong Liu, Jianming Zhang, Matthew P Patricelli, Amanda L Christie, Amy M Saur, Nancy E Kohl, Andrew L Kung, Hojong Yoon, Taebo Sim, Nathanael S Gray, James D Griffin
• Journal: Blood (Blood) Vol. 125 Issue 20 Pg. 3133-43 (May 14 2015) ISSN: 1528-0020 [Electronic] United States
• PMID: 25833960 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 by The American Society of Hematology.

Chemical References

• Antineoplastic Agents
• Bridged Bicyclo Compounds, Heterocyclic
• Germinal Center Kinases
• Membrane Proteins
• 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
• Protein Kinase Inhibitors
• Pyrimidinones
• Small Molecule Libraries
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins c-akt
• GTP Phosphohydrolases
• NRAS protein, human

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects, genetics)
• Bridged Bicyclo Compounds, Heterocyclic (pharmacology)
• Cell Cycle Checkpoints (drug effects, genetics)
• Cell Line, Tumor
• Disease Models, Animal
• Drug Screening Assays, Antitumor
• GTP Phosphohydrolases (genetics, metabolism)
• Germinal Center Kinases
• Humans
• Leukemia (drug therapy, genetics, metabolism, mortality, pathology)
• Membrane Proteins (genetics, metabolism)
• Mice
• Mutation
• Protein Kinase Inhibitors (pharmacology)
• Protein Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Pyrimidinones (pharmacology)
• Signal Transduction (drug effects)
• Small Molecule Libraries
• Xenograft Model Antitumor Assays