Oncotarget

Research Papers:

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

Zhihong Zeng, Rui-Yu Wang, Yi Hua Qiu, Duncan H. Mak, Kevin Coombes, Suk Young Yoo, Qi Zhang, Katti Jessen, Yi Liu, Christian Rommel, David A. Fruman, Hagop M. Kantarjian, Steven M. Kornblau, Michael Andreeff _ and Marina Konopleva

PDF  |  HTML  |  Supplementary Files  |  How to cite  |  Order a Reprint

Oncotarget. 2016; 7:55083-55097. https://doi.org/10.18632/oncotarget.10397

Metrics: PDF 1626 views  |   HTML 2907 views  |   ?  


Abstract

Zhihong Zeng1, Rui-Yu Wang1, Yi Hua Qiu1, Duncan H. Mak1, Kevin Coombes3, Suk Young Yoo2, Qi Zhang1, Katti Jessen4, Yi Liu5, Christian Rommel6, David A. Fruman7, Hagop M. Kantarjian1, Steven M. Kornblau1, Michael Andreeff1, Marina Konopleva1

1Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

2Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

3Department of Biomedical Informatics, Ohio State University College of Medicine, Columbus, OH, USA

4Oncology-Rinat Research & Development, San Diego, CA, USA

5Wellspring Bioscience, San Diego, CA, USA

6Roche Innovation Center Basel, Basel, Switzerland

7Institute for Immunology, and Department of Molecular Biology and Biochemistry, University of California-Irvine, Irvine, CA, USA

Correspondence to:

Michael Andreeff, email: mandreef@mdanderson.org

Marina Konopleva, email: mkonople@mdanderson.org

Keywords: mTOR, AML, stem cells, CyTOF, therapy

Received: December 29, 2015    Accepted: June 02, 2016    Published: July 04, 2016

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.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 10397