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A subset of metastatic pancreatic ductal adenocarcinomas depends quantitatively on oncogenic Kras/Mek/Erk-induced hyperactive mTOR signalling
  1. Bo Kong1,
  2. Weiwei Wu1,
  3. Tao Cheng1,
  4. Anna Melissa Schlitter2,
  5. Chengjia Qian1,
  6. Philipp Bruns1,3,
  7. Ziying Jian1,
  8. Carsten Jäger1,
  9. Ivonne Regel1,
  10. Susanne Raulefs1,
  11. Nora Behler1,
  12. Martin Irmler4,
  13. Johannes Beckers4,5,6,
  14. Helmut Friess1,
  15. Mert Erkan7,
  16. Jens T Siveke8,
  17. Andrea Tannapfel9,
  18. Stephan A Hahn10,
  19. Fabian J Theis3,
  20. Irene Esposito2,
  21. Jörg Kleeff1,
  22. Christoph W Michalski11
  1. 1Department of Surgery, Technische Universität München (TUM), Munich, Germany
  2. 2Institute of Pathology, TUM, Munich, Germany
  3. 3Institute of Computational Biology, Helmholtz-Zentrum München, Munich, Germany
  4. 4Institute of Experimental Genetics (IEG), Helmholtz-Zentrum München, Munich, Germany
  5. 5Technische Universität München, Chair of Experimental Genetics, Freising, Germany
  6. 6Deutsches Zentrum für Diabetesforschung (DZD), Neuherberg, Germany
  7. 7Department of Surgery, Koc University School of Medicine, Istanbul, Turkey
  8. 8Department of Gastroenterology, TUM, Munich, Germany
  9. 9Institute of Pathology, Ruhr-University Bochum, Bochum, Germany
  10. 10Department of Molecular Gastrointestinal Oncology, Ruhr-University Bochum, Bochum, Germany
  11. 11Department of Surgery, University of Heidelberg, Heidelberg, Germany
  1. Correspondence to Dr Christoph W Michalski, Department of Surgery, University of Heidelberg, Im Neuenheimer Feld 110, Heidelberg 69120, Germany; cwmichalski{at}


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.

Design 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.


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