Identification of novel therapeutic targets in acute leukemias with NRAS mutations using a pharmacologic approach

Title
Identification of novel therapeutic targets in acute leukemias with NRAS mutations using a pharmacologic approach
Authors
Atsushi NonamiMartin SattlerEllen WeisbergQingsong LiuJianming ZhangMatthew P. PatricelliAmanda L. ChristieAmy M. SaurNancy E. KohlAndrew L. Kung윤호종심태보Nathanael S. GrayJames D. Griffin
Keywords
NRAS
Issue Date
2015-05
Publisher
Blood
Citation
VOL 125, NO 20, 3133-3143
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.
URI
http://pubs.kist.re.kr/handle/201004/50803
ISSN
00064971
Appears in Collections:
KIST Publication > Article
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