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Preclinical efficacy of MEK inhibition in Nras-mutant AML.

Publication ,  Journal Article
Burgess, MR; Hwang, E; Firestone, AJ; Huang, T; Xu, J; Zuber, J; Bohin, N; Wen, T; Kogan, SC; Haigis, KM; Sampath, D; Lowe, S; Shannon, K; Li, Q
Published in: Blood
December 18, 2014

Oncogenic NRAS mutations are highly prevalent in acute myeloid leukemia (AML). Genetic analysis supports the hypothesis that NRAS mutations cooperate with antecedent molecular lesions in leukemogenesis, but have limited independent prognostic significance. Using short hairpin RNA-mediated knockdown in human cell lines and primary mouse leukemias, we show that AML cells with NRAS/Nras mutations are dependent on continued oncogene expression in vitro and in vivo. Using the Mx1-Cre transgene to inactivate a conditional mutant Nras allele, we analyzed hematopoiesis and hematopoietic stem and progenitor cells (HSPCs) under normal and stressed conditions and found that HSPCs lacking Nras expression are functionally equivalent to normal HSPCs in the adult mouse. Treating recipient mice transplanted with primary Nras(G12D) AMLs with 2 potent allosteric mitogen-activated protein kinase kinase (MEK) inhibitors (PD0325901 or trametinib/GlaxoSmithKline 1120212) significantly prolonged survival and reduced proliferation but did not induce apoptosis, promote differentiation, or drive clonal evolution. The phosphatidylinositol 3-kinase inhibitor GDC-0941 was ineffective as a single agent and did not augment the activity of PD0325901. All mice ultimately succumbed to progressive leukemia. Together, these data validate oncogenic N-Ras signaling as a therapeutic target in AML and support testing combination regimens that include MEK inhibitors.

Duke Scholars

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Published In

Blood

DOI

EISSN

1528-0020

Publication Date

December 18, 2014

Volume

124

Issue

26

Start / End Page

3947 / 3955

Location

United States

Related Subject Headings

  • Transgenes
  • Stem Cells
  • Signal Transduction
  • RNA, Small Interfering
  • Protein Kinase Inhibitors
  • Mutation
  • Monomeric GTP-Binding Proteins
  • Mice, Inbred C57BL
  • Mice
  • MAP Kinase Signaling System
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Burgess, M. R., Hwang, E., Firestone, A. J., Huang, T., Xu, J., Zuber, J., … Li, Q. (2014). Preclinical efficacy of MEK inhibition in Nras-mutant AML. Blood, 124(26), 3947–3955. https://doi.org/10.1182/blood-2014-05-574582
Burgess, Michael R., Eugene Hwang, Ari J. Firestone, Tannie Huang, Jin Xu, Johannes Zuber, Natacha Bohin, et al. “Preclinical efficacy of MEK inhibition in Nras-mutant AML.Blood 124, no. 26 (December 18, 2014): 3947–55. https://doi.org/10.1182/blood-2014-05-574582.
Burgess MR, Hwang E, Firestone AJ, Huang T, Xu J, Zuber J, et al. Preclinical efficacy of MEK inhibition in Nras-mutant AML. Blood. 2014 Dec 18;124(26):3947–55.
Burgess, Michael R., et al. “Preclinical efficacy of MEK inhibition in Nras-mutant AML.Blood, vol. 124, no. 26, Dec. 2014, pp. 3947–55. Pubmed, doi:10.1182/blood-2014-05-574582.
Burgess MR, Hwang E, Firestone AJ, Huang T, Xu J, Zuber J, Bohin N, Wen T, Kogan SC, Haigis KM, Sampath D, Lowe S, Shannon K, Li Q. Preclinical efficacy of MEK inhibition in Nras-mutant AML. Blood. 2014 Dec 18;124(26):3947–3955.

Published In

Blood

DOI

EISSN

1528-0020

Publication Date

December 18, 2014

Volume

124

Issue

26

Start / End Page

3947 / 3955

Location

United States

Related Subject Headings

  • Transgenes
  • Stem Cells
  • Signal Transduction
  • RNA, Small Interfering
  • Protein Kinase Inhibitors
  • Mutation
  • Monomeric GTP-Binding Proteins
  • Mice, Inbred C57BL
  • Mice
  • MAP Kinase Signaling System