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

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

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)3133-3143
Number of pages11
JournalBlood
Volume125
Issue number20
DOIs
Publication statusPublished - 2015 May 14

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Leukemia
Phosphotransferases
MAP Kinase Kinase Kinases
Mutation
Molecules
Cytotoxicity
Chemical activation
Hematologic Neoplasms
Therapeutics
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Oncogenes
Acute Myeloid Leukemia
Neoplasms
germinal center kinases

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Nonami, A., Sattler, M., Weisberg, E., Liu, Q., Zhang, J., Patricelli, M. P., ... Griffin, J. D. (2015). Identification of novel therapeutic targets in acute leukemias with NRAS mutations using a pharmacologic approach. Blood, 125(20), 3133-3143. https://doi.org/10.1182/blood-2014-12-615906

Identification of novel therapeutic targets in acute leukemias with NRAS mutations using a pharmacologic approach. / Nonami, Atsushi; Sattler, Martin; Weisberg, Ellen; Liu, Qingsong; Zhang, Jianming; Patricelli, Matthew P.; Christie, Amanda L.; Saur, Amy M.; Kohl, Nancy E.; Kung, Andrew L.; Yoon, Hojong; Sim, Taebo; Gray, Nathanael S.; Griffin, James D.

In: Blood, Vol. 125, No. 20, 14.05.2015, p. 3133-3143.

Research output: Contribution to journalArticle

Nonami, A, Sattler, M, Weisberg, E, Liu, Q, Zhang, J, Patricelli, MP, Christie, AL, Saur, AM, Kohl, NE, Kung, AL, Yoon, H, Sim, T, Gray, NS & Griffin, JD 2015, 'Identification of novel therapeutic targets in acute leukemias with NRAS mutations using a pharmacologic approach', Blood, vol. 125, no. 20, pp. 3133-3143. https://doi.org/10.1182/blood-2014-12-615906
Nonami, Atsushi ; Sattler, Martin ; Weisberg, Ellen ; Liu, Qingsong ; Zhang, Jianming ; Patricelli, Matthew P. ; Christie, Amanda L. ; Saur, Amy M. ; Kohl, Nancy E. ; Kung, Andrew L. ; Yoon, Hojong ; Sim, Taebo ; Gray, Nathanael S. ; Griffin, James D. / Identification of novel therapeutic targets in acute leukemias with NRAS mutations using a pharmacologic approach. In: Blood. 2015 ; Vol. 125, No. 20. pp. 3133-3143.
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