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Targeting mTOR dependency in pancreatic cancer
  1. Douglas C Morran1,
  2. Jianmin Wu2,
  3. Nigel B Jamieson3,
  4. Agata Mrowinska1,
  5. Gabriela Kalna1,
  6. Saadia A Karim1,
  7. Amy Y M Au1,
  8. Christopher J Scarlett4,
  9. David K Chang2,3,5,6,7,
  10. Malgorzata Z Pajak1,
  11. Karin A Oien1,8,
  12. Colin J McKay3,
  13. C Ross Carter3,
  14. Gerry Gillen9,
  15. Sue Champion10,
  16. Sally L Pimlott10,
  17. Kurt I Anderson1,
  18. T R Jeffry Evans1,8,
  19. Sean M Grimmond7,11,
  20. Andrew V Biankin2,3,5,6,7,
  21. Owen J Sansom1,
  22. Australian Pancreatic Cancer Genome Initiative (APGI),
  23. Jennifer P Morton1
  1. 1CRUK Beatson Institute, Glasgow, UK
  2. 2The Kinghorn Cancer Centre and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia
  3. 3West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK
  4. 4School of Environmental & Life Sciences, University of Newcastle, Ourimbah, New South Wales, Australia
  5. 5Department of Surgery, Bankstown Hospital, Bankstown, Sydney, New South Wales, Australia
  6. 6Faculty of Medicine, South Western Sydney Clinical School, University of NSW, Liverpool, New South Wales, Australia
  7. 7The Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
  8. 8Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
  9. 9West of Scotland PET Centre, Gartnavel General Hospital, Glasgow, UK
  10. 10West of Scotland Radionuclide Dispensary, NHS Greater Glasgow and Clyde, Glasgow, UK
  11. 11Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, St Lucia, Brisbane, Queensland, Australia
  1. Correspondence to Dr Jennifer P Morton, Cancer Research UK Beatson Institute, Garscube Estate, Switchback Rd, Glasgow G61 1BD, UK; j.morton{at}beatson.gla.ac.uk

Abstract

Objective Pancreatic cancer is a leading cause of cancer-related death in the Western world. Current chemotherapy regimens have modest survival benefit. Thus, novel, effective therapies are required for treatment of this disease.

Design Activating KRAS mutation almost always drives pancreatic tumour initiation, however, deregulation of other potentially druggable pathways promotes tumour progression. PTEN loss leads to acceleration of KrasG12D-driven pancreatic ductal adenocarcinoma (PDAC) in mice and these tumours have high levels of mammalian target of rapamycin (mTOR) signalling. To test whether these KRAS PTEN pancreatic tumours show mTOR dependence, we compared response to mTOR inhibition in this model, to the response in another established model of pancreatic cancer, KRAS P53. We also assessed whether there was a subset of pancreatic cancer patients who may respond to mTOR inhibition.

Results We found that tumours in KRAS PTEN mice exhibit a remarkable dependence on mTOR signalling. In these tumours, mTOR inhibition leads to proliferative arrest and even tumour regression. Further, we could measure response using clinically applicable positron emission tomography imaging. Importantly, pancreatic tumours driven by activated KRAS and mutant p53 did not respond to treatment. In human tumours, approximately 20% of cases demonstrated low PTEN expression and a gene expression signature that overlaps with murine KRAS PTEN tumours.

Conclusions KRAS PTEN tumours are uniquely responsive to mTOR inhibition. Targeted anti-mTOR therapies may offer clinical benefit in subsets of human PDAC selected based on genotype, that are dependent on mTOR signalling. Thus, the genetic signatures of human tumours could be used to direct pancreatic cancer treatment in the future.

  • Pancreatic Cancer
  • Pharmacogenomics
  • Cell Signalling
  • Genetics

This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 3.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/3.0/

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