Unknown

Dataset Information

0

MLN0128, a novel mTOR kinase inhibitor, disrupts survival signaling and triggers apoptosis in AML and AML stem/ progenitor cells.


ABSTRACT: 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.

SUBMITTER: Zeng Z 

PROVIDER: S-EPMC5342403 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

altmetric image

Publications

MLN0128, a novel mTOR kinase inhibitor, disrupts survival signaling and triggers apoptosis in AML and AML stem/ progenitor cells.

Zeng Zhihong Z   Wang Rui-Yu RY   Qiu Yi Hua YH   Mak Duncan H DH   Coombes Kevin K   Yoo Suk Young SY   Zhang Qi Q   Jessen Katti K   Liu Yi Y   Rommel Christian C   Fruman David A DA   Kantarjian Hagop M HM   Kornblau Steven M SM   Andreeff Michael M   Konopleva Marina M  

Oncotarget 20160801 34


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 in  ...[more]

Similar Datasets

| S-EPMC3593948 | biostudies-literature
| S-EPMC4248662 | biostudies-literature
| S-EPMC5696057 | biostudies-literature
| S-EPMC6026053 | biostudies-literature
| S-EPMC6452902 | biostudies-literature
| S-EPMC4872734 | biostudies-literature
| S-EPMC3460689 | biostudies-literature
| S-EPMC4365782 | biostudies-literature
| S-EPMC4332837 | biostudies-literature
| S-EPMC6050986 | biostudies-literature