title: A subset of metastatic pancreatic ductal adenocarcinomas depends quantitatively on oncogenic Kras/Mek/Erk-induced hyperactive mTOR signalling.
abstract: OBJECTIVE
  Oncogenic Kras-activated robust Mek/Erk signals phosphorylate to the tuberous sclerosis complex (Tsc) and deactivates mammalian target of rapamycin (mTOR) suppression in pancreatic ductal adenocarcinoma (PDAC); however, Mek and mTOR inhibitors alone have demonstrated minimal clinical antitumor activity.
  
  
  METHODS
  We generated transgenic mouse models in which mTOR was hyperactivated either through the Kras/Mek/Erk cascade, by loss of Pten or through Tsc1 haploinsufficiency. Primary cancer cells were isolated from mouse tumours. Oncogenic signalling was assessed in vitro and in vivo, with and without single or multiple targeted molecule inhibition. Transcriptional profiling was used to identify biomarkers predictive of the underlying pathway alterations and of therapeutic response. Results from the preclinical models were confirmed on human material.
  
  
  RESULTS
  Reduction of Tsc1 function facilitated activation of Kras/Mek/Erk-mediated mTOR signalling, which promoted the development of metastatic PDACs. Single inhibition of mTOR or Mek elicited strong feedback activation of Erk or Akt, respectively. Only dual inhibition of Mek and PI3K reduced mTOR activity and effectively induced cancer cell apoptosis. Analysis of downstream targets demonstrated that oncogenic activity of the Mek/Erk/Tsc/mTOR axis relied on Aldh1a3 function. Moreover, in clinical PDAC samples, ALDH1A3 specifically labelled an aggressive subtype.
  
  
  CONCLUSIONS
  These results advance our understanding of Mek/Erk-driven mTOR activation and its downstream targets in PDAC, and provide a mechanistic rationale for effective therapeutic matching for Aldh1a3-positive PDACs.
authors.affiliation: Department of Surgery, Technische Universität München (TUM), Munich, Germany.
authors.forename: Bo
authors.initials: B
authors.lastname: Kong
authors.affiliation: Department of Surgery, Technische Universität München (TUM), Munich, Germany.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Wu
authors.affiliation: Department of Surgery, Technische Universität München (TUM), Munich, Germany.
authors.forename: Tao
authors.initials: T
authors.lastname: Cheng
authors.affiliation: Institute of Pathology, TUM, Munich, Germany.
authors.forename: Anna Melissa
authors.initials: AM
authors.lastname: Schlitter
authors.affiliation: Department of Surgery, Technische Universität München (TUM), Munich, Germany.
authors.forename: Chengjia
authors.initials: C
authors.lastname: Qian
authors.affiliation: Department of Surgery, Technische Universität München (TUM), Munich, Germany Institute of Computational Biology, Helmholtz-Zentrum München, Munich, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Bruns
authors.affiliation: Department of Surgery, Technische Universität München (TUM), Munich, Germany.
authors.forename: Ziying
authors.initials: Z
authors.lastname: Jian
authors.affiliation: Department of Surgery, Technische Universität München (TUM), Munich, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Jäger
authors.affiliation: Department of Surgery, Technische Universität München (TUM), Munich, Germany.
authors.forename: Ivonne
authors.initials: I
authors.lastname: Regel
authors.affiliation: Department of Surgery, Technische Universität München (TUM), Munich, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Raulefs
authors.affiliation: Department of Surgery, Technische Universität München (TUM), Munich, Germany.
authors.forename: Nora
authors.initials: N
authors.lastname: Behler
authors.affiliation: Institute of Experimental Genetics (IEG), Helmholtz-Zentrum München, Munich, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Irmler
authors.affiliation: Institute of Experimental Genetics (IEG), Helmholtz-Zentrum München, Munich, Germany Technische Universität München, Chair of Experimental Genetics, Freising, Germany Deutsches Zentrum für Diabetesforschung (DZD), Neuherberg, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Beckers
authors.affiliation: Department of Surgery, Technische Universität München (TUM), Munich, Germany.
authors.forename: Helmut
authors.initials: H
authors.lastname: Friess
authors.affiliation: Department of Surgery, Koc University School of Medicine, Istanbul, Turkey.
authors.forename: Mert
authors.initials: M
authors.lastname: Erkan
authors.affiliation: Department of Gastroenterology, TUM, Munich, Germany.
authors.forename: Jens T
authors.initials: JT
authors.lastname: Siveke
authors.affiliation: Institute of Pathology, Ruhr-University Bochum, Bochum, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Tannapfel
authors.affiliation: Department of Molecular Gastrointestinal Oncology, Ruhr-University Bochum, Bochum, Germany.
authors.forename: Stephan A
authors.initials: SA
authors.lastname: Hahn
authors.affiliation: Institute of Computational Biology, Helmholtz-Zentrum München, Munich, Germany.
authors.forename: Fabian J
authors.initials: FJ
authors.lastname: Theis
authors.affiliation: Institute of Pathology, TUM, Munich, Germany.
authors.forename: Irene
authors.initials: I
authors.lastname: Esposito
authors.affiliation: Department of Surgery, Technische Universität München (TUM), Munich, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Kleeff
authors.affiliation: Department of Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Christoph W
authors.initials: CW
authors.lastname: Michalski
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis; D063646:Carcinogenesis / Q000378:metabolism / Q000473:pathology*; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases; D010766:Phosphorylation; D016283:Proto-Oncogene Proteins p21(ras) / Q000502:physiology*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000502:physiology*
chemical_list: D014408:Biomarkers, Tumor; D019869:Phosphatidylinositol 3-Kinases; D016283:Proto-Oncogene Proteins p21(ras); D058570:TOR Serine-Threonine Kinases; C117307:KRAS protein, human; C546842:MTOR protein, human; C546843:mTOR protein, mouse; C495971:Hras protein, mouse
keywords: ONCOGENES; PANCREATIC CANCER; PANCREATIC PATHOLOGY