title: The novel combination of dual mTOR inhibitor AZD2014 and pan-PIM inhibitor AZD1208 inhibits growth in acute myeloid leukemia via HSF pathway suppression.
abstract: Mammalian target of rapamycin (mTOR) signaling is a critical pathway in the biology of acute myeloid leukemia (AML). Proviral integration site for moloney murine leukemia virus (PIM) serine/threonine kinase signaling takes part in various pathways exerting tumorigenic properties. We hypothesized that the combination of a PIM kinase inhibitor with an mTOR inhibitor might have complementary growth-inhibitory effects against AML. The simultaneous inhibition of the PIM kinase by pan-PIM inhibitor AZD1208 and of mTOR by selective mTORC1/2 dual inhibitor AZD2014 exerted anticancer properties in AML cell lines and in cells derived from primary AML samples with or without supportive stromal cell co-culture, leading to suppressed proliferation and increased apoptosis. The combination of AZD1208 and AZD2014 rapidly activated AMPKα, a negative regulator of translation machinery through mTORC1/2 signaling in AML cells; profoundly inhibited AKT and 4EBP1 activation; and suppressed polysome formation. Inhibition of both mTOR and PIM counteracted induction of heat-shock family proteins, uncovering the master negative regulation of heat shock factor 1 (HSF1), the dominant transcription factor controlling cellular stress responses. The novel combination of the dual mTOR inhibitor and pan-PIM inhibitor synergistically inhibited AML growth by effectively reducing protein synthesis through heat shock factor pathway suppression.
authors.affiliation: Research Institute for Environmental and Gender Specific Medicine, Juntendo University of Medicine, Tokyo, Japan.|Department of Laboratory Medicine, Juntendo University of Medicine, Tokyo, Japan.
authors.forename: Masako
authors.initials: M
authors.lastname: Harada
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Juliana
authors.initials: J
authors.lastname: Benito
authors.affiliation: Department of Laboratory Medicine, Juntendo University of Medicine, Tokyo, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Yamamoto
authors.affiliation: Division of Hematology-Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Medical School, Chicago, Illinois, USA.
authors.forename: Surinder
authors.initials: S
authors.lastname: Kaur
authors.affiliation: Division of Hematology-Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Medical School, Chicago, Illinois, USA.
authors.forename: Dirim
authors.initials: D
authors.lastname: Arslan
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Santiago
authors.initials: S
authors.lastname: Ramirez
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Jacamo
authors.affiliation: Division of Hematology-Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Medical School, Chicago, Illinois, USA.
authors.forename: Leonidas
authors.initials: L
authors.lastname: Platanias
authors.affiliation: Department of Laboratory Medicine, Tokai University School of Medicine, Kanagawa, Japan.
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Matsushita
authors.affiliation: BioMedical Research Center, Juntendo University of Medicine, Tokyo, Japan.|Laboratory of Bioanalytical Chemistry, Tohoku Pharmaceutical University, Miyagi, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Fujimura
authors.affiliation: BioMedical Research Center, Juntendo University of Medicine, Tokyo, Japan.
authors.forename: Saiko
authors.initials: S
authors.lastname: Kazuno
authors.affiliation: Hematology, Respiratory Medicine and Oncology, Department of Medicine, Saga University, Saga, Japan.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Kojima
authors.affiliation: Department of Laboratory Medicine, Juntendo University of Medicine, Tokyo, Japan.|Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Tabe
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Konopleva
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D001713:Biphenyl Compounds / Q000494:pharmacology*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004359:Drug Therapy, Combination; D005434:Flow Cytometry; D000076249:Heat Shock Transcription Factors; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D009025:Morpholines / Q000494:pharmacology*; D010750:Phosphoproteins; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors*; D011743:Pyrimidines; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D053778:Thiazolidines / Q000494:pharmacology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: C587575:AZD1208; D001549:Benzamides; D001713:Biphenyl Compounds; D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D000076249:Heat Shock Transcription Factors; D009025:Morpholines; D010750:Phosphoproteins; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D012333:RNA, Messenger; D053778:Thiazolidines; D014157:Transcription Factors; C585537:vistusertib; C546842:MTOR protein, human; D051573:Proto-Oncogene Proteins c-pim-1; D058570:TOR Serine-Threonine Kinases; C406031:proto-oncogene proteins pim
keywords: PIM inhibitor; acute myeloid leukemia (AML); heat shock factor (HSF); mTORC1/2 dual inhibitor