title: Dual PI3K/mTOR inhibition shows antileukemic activity in MLL-rearranged acute myeloid leukemia.
abstract: In acute myeloid leukemia (AML), several signaling pathways such as the phosphatidylinositol-3-kinase/AKT and the mammalian target of rapamycin (PI3K/AKT/mTOR) pathway are deregulated and constitutively activated as a consequence of genetic and cytogenetic abnormalities. We tested the effectiveness of PI3K/AKT/mTOR-targeting therapies and tried to identify alterations that associate with treatment sensitivity. By analyzing primary samples and cell lines, we observed a wide range of cytotoxic activity for inhibition of AKT (MK-2206), mTORC1 (rapamycin) and PI3K/mTORC1/2 (BEZ-235) with a high sensitivity of cells carrying an MLL rearrangement. In vivo PI3K/mTOR inhibition delayed tumor progression, reduced tumor load and prolonged survival in an MLL-AF9(+)/FLT3-ITD(+) xenograft mouse model. By performing targeted amplicon sequencing in 38 MLL-AF9(+) and 125 cytogenetically normal AML patient samples, we found a high additional mutation rate for genes involved in growth factor signaling in 79% of all MLL-AF9(+) samples, which could lead to a possible benefit of this cohort. PI3K/mTOR inhibition for 24 h led to the cross-activation of the ERK pathway. Further in vitro studies combining PI3K/mTOR and ERK pathway inhibition revealed highly synergistic effects in apoptosis assays. Our data implicate a possible therapeutic benefit of PI3K/mTOR inhibition in the MLL-mutated subgroup. Inhibiting rescue pathways could improve the therapeutic efficacy of PI3K-targeted therapies in AML.
authors.affiliation: 1] Department of Internal Medicine III, University Hospital Grosshadern, Ludwig Maximilians University (LMU), Munich, Germany [2] Clinical Cooperative Group Leukemia, Helmholtz Center Munich for Environmental Health, Munich, Germany [3] German Cancer Consortium (DKTK), Heidelberg, Germany [4] German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Sandhöfer
authors.affiliation: 1] Department of Internal Medicine III, University Hospital Grosshadern, Ludwig Maximilians University (LMU), Munich, Germany [2] Clinical Cooperative Group Leukemia, Helmholtz Center Munich for Environmental Health, Munich, Germany.
authors.forename: K H
authors.initials: KH
authors.lastname: Metzeler
authors.affiliation: Department of Internal Medicine III, University Hospital Grosshadern, Ludwig Maximilians University (LMU), Munich, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Rothenberg
authors.affiliation: 1] Department of Internal Medicine III, University Hospital Grosshadern, Ludwig Maximilians University (LMU), Munich, Germany [2] Clinical Cooperative Group Leukemia, Helmholtz Center Munich for Environmental Health, Munich, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Herold
authors.affiliation: Department of Gene Vectors, Helmholtz Center Munich for Environmental Health, Munich, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Tiedt
authors.affiliation: Department of Gene Vectors, Helmholtz Center Munich for Environmental Health, Munich, Germany.
authors.forename: V
authors.initials: V
authors.lastname: Groiß
authors.affiliation: Department of Gene Vectors, Helmholtz Center Munich for Environmental Health, Munich, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Carlet
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Walter
authors.affiliation: Center for Human Genetics and Laboratory Medicine, Martinsried, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Hinrichsen
authors.affiliation: Center for Human Genetics and Laboratory Medicine, Martinsried, Germany.
authors.forename: O
authors.initials: O
authors.lastname: Wachter
authors.affiliation: Department of Gene Vectors, Helmholtz Center Munich for Environmental Health, Munich, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Grunert
authors.affiliation: Department of Internal Medicine III, University Hospital Grosshadern, Ludwig Maximilians University (LMU), Munich, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Schneider
authors.affiliation: Department of Internal Medicine III, University Hospital Grosshadern, Ludwig Maximilians University (LMU), Munich, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Subklewe
authors.affiliation: Department of Internal Medicine III, University Hospital Grosshadern, Ludwig Maximilians University (LMU), Munich, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Dufour
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Fröhling
authors.affiliation: Center for Human Genetics and Laboratory Medicine, Martinsried, Germany.
authors.forename: H-G
authors.initials: HG
authors.lastname: Klein
authors.affiliation: 1] Department of Internal Medicine III, University Hospital Grosshadern, Ludwig Maximilians University (LMU), Munich, Germany [2] Clinical Cooperative Group Leukemia, Helmholtz Center Munich for Environmental Health, Munich, Germany [3] German Cancer Consortium (DKTK), Heidelberg, Germany [4] German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Hiddemann
authors.affiliation: 1] German Cancer Consortium (DKTK), Heidelberg, Germany [2] German Cancer Research Center (DKFZ), Heidelberg, Germany [3] Department of Gene Vectors, Helmholtz Center Munich for Environmental Health, Munich, Germany [4] Department of Oncology, Dr von Haunersches Kinderspital, Ludwig Maximilians University (LMU), Munich, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Jeremias
authors.affiliation: 1] Department of Internal Medicine III, University Hospital Grosshadern, Ludwig Maximilians University (LMU), Munich, Germany [2] Clinical Cooperative Group Leukemia, Helmholtz Center Munich for Environmental Health, Munich, Germany [3] German Cancer Consortium (DKTK), Heidelberg, Germany [4] German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Spiekermann
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D004357:Drug Synergism; D015973:Gene Expression Regulation, Leukemic; D015321:Gene Rearrangement; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D016019:Survival Analysis; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D006575:Heterocyclic Compounds, 3-Ring; D007093:Imidazoles; D051788:Myeloid-Lymphoid Leukemia Protein; D015514:Oncogene Proteins, Fusion; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011804:Quinolines; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C548887:MK 2206; C474558:MLL-AF9 fusion protein, human; C546842:MTOR protein, human; C531198:dactolisib