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  • Title: MLN0128, a novel mTOR kinase inhibitor, disrupts survival signaling and triggers apoptosis in AML and AML stem/ progenitor cells.
    Author: Zeng Z, Wang RY, Qiu YH, Mak DH, Coombes K, Yoo SY, Zhang Q, Jessen K, Liu Y, Rommel C, Fruman DA, Kantarjian HM, Kornblau SM, Andreeff M, Konopleva M.
    Journal: Oncotarget; 2016 Aug 23; 7(34):55083-55097. PubMed ID: 27391151.
    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.
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