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.
Bibliographical noteFunding Information:
This study is supported by the National Institutes of Health, National Cancer Institute grants CA66996 (J.D.G), CA130876-04 (N.S.G), and CA154303-01A1 (N.S.G), and HG005693-01 (N.S.G), a grant from the Kanae foundation for the promotion of medical science (A.N.), and grants from the Korea Institute of Science and Technology (T.S.), the creative/challenging research program of the National Research Foundation of Korea (NRF-2011-0028676) (T.S.), and the Korea Basic Science Institute (D33400, T.S.).
© 2015 by The American Society of Hematology.
ASJC Scopus subject areas
- Cell Biology