title: 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.
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Zeng
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Rui-Yu
authors.initials: RY
authors.lastname: Wang
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Yi Hua
authors.initials: YH
authors.lastname: Qiu
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Duncan H
authors.initials: DH
authors.lastname: Mak
authors.affiliation: Department of Biomedical Informatics, Ohio State University College of Medicine, Columbus, OH, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Coombes
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Suk Young
authors.initials: SY
authors.lastname: Yoo
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Oncology-Rinat Research & Development, San Diego, CA, USA.
authors.forename: Katti
authors.initials: K
authors.lastname: Jessen
authors.affiliation: Wellspring Bioscience, San Diego, CA, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Roche Innovation Center Basel, Basel, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Rommel
authors.affiliation: Institute for Immunology, and Department of Molecular Biology and Biochemistry, University of California-Irvine, Irvine, CA, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Fruman
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Hagop M
authors.initials: HM
authors.lastname: Kantarjian
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Kornblau
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Andreeff
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Konopleva
mesh_terms: D000208:Acute Disease; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001583:Benzoxazoles / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000378:metabolism; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020298:U937 Cells; D023041:Xenograft Model Antitumor Assays / Q000379:methods; D000225:Adenine / Q000031:analogs & derivatives
chemical_list: D001583:Benzoxazoles; D051057:Proto-Oncogene Proteins c-akt; D011743:Pyrimidines; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human; C572449:sapanisertib; D000225:Adenine
keywords: AML; CyTOF; mTOR; stem cells; therapy