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MTOR inhibitor-based combination therapies for pancreatic cancer

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Abstract

Background:

Although the mechanistic target of rapamycin (MTOR) kinase, included in the mTORC1 and mTORC2 signalling hubs, has been demonstrated to be active in a significant fraction of patients with pancreatic ductal adenocarcinoma (PDAC), the value of the kinase as a therapeutic target needs further clarification.

Methods:

We used Mtor floxed mice to analyse the function of the kinase in context of the pancreas at the genetic level. Using a dual-recombinase system, which is based on the flippase-FRT (Flp-FRT) and Cre-loxP recombination technologies, we generated a novel cellular model, allowing the genetic analysis of MTOR functions in tumour maintenance. Cross-species validation and pharmacological intervention studies were used to recapitulate genetic data in human models, including primary human 3D PDAC cultures.

Results:

Genetic deletion of the Mtor gene in the pancreas results in exocrine and endocrine insufficiency. In established murine PDAC cells, MTOR is linked to metabolic pathways and maintains the glucose uptake and growth. Importantly, blocking MTOR genetically as well as pharmacologically results in adaptive rewiring of oncogenic signalling with activation of canonical extracellular signal-regulated kinase and phosphoinositide 3-kinase-AKT pathways. We provide evidence that interfering with such adaptive signalling in murine and human PDAC models is important in a subgroup.

Conclusions:

Our data suggest developing dual MTORC1/TORC2 inhibitor-based therapies for subtype-specific intervention.

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Acknowledgements

We thank Dr P Soriano and Dr L Luo for providing mouse lines. We thank Dr A Bradley for support and help during the transfer of mouse lines. We thank the Z1 Project of the SFB824 for providing radiotracers. The depicted results of Supplementary Figure 7C are in whole based on data that were generated by the TCGA Research Network: http://cancergenome.nih.gov/. This work was supported by the Deutsche Forschungsgemeinschaft (DFG) (SFB824/C9 to GS and DS; SCHN 959/3-1 to GS), Deutsche Krebshilfe (111273 (Max-Eder Program) to MR), Wilhelm-Sander Foundation (2016.004.1 to GS), DKTK Joint Funding (to RR, DS, WW and GS), Else-Kröner-Fresenius-Stiftung (to 2016_A43 to MW).

Author information

Affiliations

  1. Medical Clinic and Polyclinic II, Klinikum rechts der Isar, Technical University Munich, 81675 München, Germany

    • Zonera Hassan
    • , Christian Schneeweis
    • , Christian Veltkamp
    • , Zahra Dantes
    • , Roland M Schmid
    • , Roland Rad
    • , Maximilian Reichert
    • , Dieter Saur
    •  & Günter Schneider
  2. Institute of Pathology, Heinrich-Heine University and University Hospital Düsseldorf, 40225 Düsseldorf, Germany

    • Matthias Wirth
  3. Department of Nuclear Medicine, Klinikum rechts der Isar, Technical University Munich, 81675 München, Germany

    • Benedikt Feuerecker
  4. German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), 69120 Heidelberg, Germany

    • Benedikt Feuerecker
    • , Roland Rad
    • , Dieter Saur
    •  & Günter Schneider
  5. Department of Surgery, Klinikum rechts der Isar, Technical University of Munich, 81675 München, Germany

    • Güralp O Ceyhan
  6. Molecular Biology, Centre for Medical Biotechnology (ZMB), University Duisburg-Essen, 45141 Essen, Germany

    • Shirley K Knauer
  7. Institute of Pathology, Technische Universität München, 81675 München, Germany

    • Wilko Weichert
  8. Molecular and Cellular Oncology/ENT, University Medical Center Mainz, Langenbeckstrasse 1, Mainz 55131, Germany

    • Roland Stauber
  9. Laboratory of Molecular Gastroenterology and Hepatology, 1st Department of Internal Medicine, University Hospital Schleswig-Holstein, Kiel, Germany

    • Alexander Arlt
  10. Department of Toxicology, University of Mainz Medical Center, Mainz 55131, Germany

    • Oliver H Krämer
  11. Division of Gastroenterology and Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA

    • Maximilian Reichert

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Competing interests

The authors declare no conflict of interest.

Corresponding author

Correspondence to Günter Schneider.

Supplementary information

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Supplementary Information accompanies this paper on British Journal of Cancer website (http://www.nature.com/bjc)