期刊
ONCOTARGET
卷 7, 期 34, 页码 55083-55097出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.10397
关键词
mTOR; AML; stem cells; CyTOF; therapy
资金
- NCI NIH HHS [R01 CA163481, P30 CA016672, R01 CA155056, P50 CA100632, R01 CA158383, P01 CA055164, P30 CA016058] Funding Source: Medline
mTOR activation leads to enhanced survival signaling in acute myeloid leukemia ( AML) cells. The active-site mTOR inhibitors ( asTORi) represent a promising new approach to targeting mTOR in AKT/mTOR signaling. MLN0128 is an orally-administered, second-generation asTORi, currently in clinical development. We examined the anti-leukemic effects and the mechanisms of action of MLN0128 in AML cell lines and primary samples, with a particular focus on its effect in AML stem/progenitor cells. MLN0128 inhibited cell proliferation and induced apoptosis in AML by attenuating the activity of mTOR complex 1 and 2. Using time-of-flight mass cytometry, we demonstrated that MLN0128 selectively targeted and functionally inhibited AML stem/progenitor cells with high AKT/mTOR signaling activity. Using the reverse-phase protein array technique, we measured expression and phosphorylation changes in response to MLN0128 in 151 proteins from 24 primary AML samples and identified several pro-survival pathways that antagonize MLN0128-induced cellular stress. A combined blockade of AKT/mTOR signaling and these pro-survival pathways facilitated AML cell killing. Our findings provide a rationale for the clinical use of MLN0128 to target AML and AML stem/progenitor cells, and support the use of combinatorial multi-targeted approaches in AML therapy.
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