Preclinical efficacy of MEK inhibition in Nras-mutant AML

被引:84
|
作者
Burgess, Michael R. [1 ]
Hwang, Eugene [2 ]
Firestone, Ari J. [2 ]
Huang, Tannie [2 ]
Xu, Jin [2 ]
Zuber, Johannes [3 ]
Bohin, Natacha [4 ]
Wen, Tiffany [4 ]
Kogan, Scott C. [5 ]
Haigis, Kevin M. [6 ,7 ]
Sampath, Deepak [8 ]
Lowe, Scott [9 ,10 ]
Shannon, Kevin [2 ,5 ,11 ]
Li, Qing [4 ]
机构
[1] Univ Calif San Francisco, Dept Med, Div Hematol Oncol, San Francisco, CA 94158 USA
[2] Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94158 USA
[3] Res Inst Mol Pathol, A-1030 Vienna, Austria
[4] Univ Michigan, Dept Med, Div Hematol Oncol, Ann Arbor, MI 48109 USA
[5] Univ Calif San Francisco, San Francisco, CA 94158 USA
[6] Massachusetts Gen Hosp, Mol Pathol Unit, Charlestown, MA USA
[7] Massachusetts Gen Hosp, Ctr Canc Res, Charlestown, MA USA
[8] Genentech Inc, Dept Translat Oncol, San Francisco, CA 94080 USA
[9] Howard Hughes Med Inst, New York, NY USA
[10] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA
[11] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94158 USA
基金
美国国家卫生研究院;
关键词
ACUTE MYELOID-LEUKEMIA; SMALL-MOLECULE INHIBITION; HEMATOPOIETIC STEM; MYELODYSPLASTIC SYNDROME; HYPERACTIVE RAS; TARGETING RAS; PHASE-I; MUTATIONS; CANCER; GENE;
D O I
10.1182/blood-2014-05-574582
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
引用
收藏
页码:3947 / 3955
页数:9
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