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

Abstract

// Zhihong Zeng 1 , Rui-Yu Wang 1 , Yi Hua Qiu 1 , Duncan H. Mak 1 , Kevin Coombes 3 , Suk Young Yoo 2 , Qi Zhang 1 , Katti Jessen 4 , Yi Liu 5 , Christian Rommel 6 , David A. Fruman 7 , Hagop M. Kantarjian 1 , Steven M. Kornblau 1 , Michael Andreeff 1 , Marina Konopleva 1 1 Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 2 Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 3 Department of Biomedical Informatics, Ohio State University College of Medicine, Columbus, OH, USA 4 Oncology-Rinat Research & Development, San Diego, CA, USA 5 Wellspring Bioscience, San Diego, CA, USA 6 Roche Innovation Center Basel, Basel, Switzerland 7 Institute 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.