Author(s)

D. C. Morran, J. Wu, N. B. Jamieson, A. Mrowinska, G. Kalna, S. A. Karim, A. Y. Au, C. J. Scarlett, D. K. Chang, M. Z. Pajak, K. A. Oien, C. J. McKay, C. R. Carter, G. Gillen, S. Champion, S. L. Pimlott, K. I. Anderson, T. R. Evans, S. M. Grimmond, A. V. Biankin, O. J. Sansom, J. P. Morton

ISBN

Publication year

2014

Periodical

Gut

Periodical Number

1468-3288 (Electronic)

Volume

Pages

Author Address

CRUK Beatson Institute, Glasgow, UK. FAU - Wu, Jianmin The Kinghorn Cancer Centre and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia. FAU - Jamieson, Nigel B West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK. FAU - Mrowinska, Agata CRUK Beatson Institute, Glasgow, UK. FAU - Kalna, Gabriela CRUK Beatson Institute, Glasgow, UK. FAU - Karim, Saadia A CRUK Beatson Institute, Glasgow, UK. FAU - Au, Amy Y M CRUK Beatson Institute, Glasgow, UK. FAU - Scarlett, Christopher J School of Environmental & Life Sciences, University of Newcastle, Ourimbah, New South Wales, Australia. FAU - Chang, David K The Kinghorn Cancer Centre and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK Department of Surgery, Bankstown Hospital, Bankstown, Sydney, New South Wales, Australia Faculty of Medicine, South Western Sydney Clinical School, University of NSW, Liverpool, New South Wales, Australia The Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK. FAU - Pajak, Malgorzata Z CRUK Beatson Institute, Glasgow, UK. CRUK Beatson Institute, Glasgow, UK Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK. FAU - McKay, Colin J West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK. FAU - Carter, C Ross West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK. FAU - Gillen, Gerry West of Scotland PET Centre, Gartnavel General Hospital, Glasgow, UK. FAU - Champion, Sue West of Scotland Radionuclide Dispensary, NHS Greater Glasgow and Clyde, Glasgow, UK. FAU - Pimlott, Sally L West of Scotland Radionuclide Dispensary, NHS Greater Glasgow and Clyde, Glasgow, UK. FAU - Anderson, Kurt I CRUK Beatson Institute, Glasgow, UK. FAU - Evans, T R Jeffry CRUK Beatson Institute, Glasgow, UK Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK. FAU - Grimmond, Sean M The Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, St Lucia, Brisbane, Queensland, Australia. FAU - Biankin, Andrew V The Kinghorn Cancer Centre and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK Department of Surgery, Bankstown Hospital, Bankstown, Sydney, New South Wales, Australia Faculty of Medicine, South Western Sydney Clinical School, University of NSW, Liverpool, New South Wales, Australia The Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK. FAU - Sansom, Owen J CRUK Beatson Institute, Glasgow, UK. FAU - Morton, Jennifer P

Full version

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 Kras(G12D)-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.