PMID- 24717934 OWN - NLM STAT- MEDLINE DCOM- 20140930 LR - 20240210 IS - 1468-3288 (Electronic) IS - 0017-5749 (Print) IS - 0017-5749 (Linking) VI - 63 IP - 9 DP - 2014 Sep TI - Targeting mTOR dependency in pancreatic cancer. PG - 1481-9 LID - 10.1136/gutjnl-2013-306202 [doi] AB - 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. CI - Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions. FAU - Morran, Douglas C AU - Morran DC AD - CRUK Beatson Institute, Glasgow, UK. FAU - Wu, Jianmin AU - Wu J AD - The Kinghorn Cancer Centre and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia. FAU - Jamieson, Nigel B AU - Jamieson NB AD - West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK. FAU - Mrowinska, Agata AU - Mrowinska A AD - CRUK Beatson Institute, Glasgow, UK. FAU - Kalna, Gabriela AU - Kalna G AD - CRUK Beatson Institute, Glasgow, UK. FAU - Karim, Saadia A AU - Karim SA AD - CRUK Beatson Institute, Glasgow, UK. FAU - Au, Amy Y M AU - Au AY AD - CRUK Beatson Institute, Glasgow, UK. FAU - Scarlett, Christopher J AU - Scarlett CJ AD - School of Environmental & Life Sciences, University of Newcastle, Ourimbah, New South Wales, Australia. FAU - Chang, David K AU - Chang DK AD - 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 AU - Pajak MZ AD - CRUK Beatson Institute, Glasgow, UK. CN - Australian Pancreatic Cancer Genome Initiative (APGI) FAU - Oien, Karin A AU - Oien KA AD - 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 AU - McKay CJ AD - West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK. FAU - Carter, C Ross AU - Carter CR AD - West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK. FAU - Gillen, Gerry AU - Gillen G AD - West of Scotland PET Centre, Gartnavel General Hospital, Glasgow, UK. FAU - Champion, Sue AU - Champion S AD - West of Scotland Radionuclide Dispensary, NHS Greater Glasgow and Clyde, Glasgow, UK. FAU - Pimlott, Sally L AU - Pimlott SL AD - West of Scotland Radionuclide Dispensary, NHS Greater Glasgow and Clyde, Glasgow, UK. FAU - Anderson, Kurt I AU - Anderson KI AD - CRUK Beatson Institute, Glasgow, UK. FAU - Evans, T R Jeffry AU - Evans TR AD - 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 AU - Grimmond SM AD - 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 AU - Biankin AV AD - 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 AU - Sansom OJ AD - CRUK Beatson Institute, Glasgow, UK. FAU - Morton, Jennifer P AU - Morton JP AD - CRUK Beatson Institute, Glasgow, UK. LA - eng GR - 12481/CRUK_/Cancer Research UK/United Kingdom GR - 15565/CRUK_/Cancer Research UK/United Kingdom GR - MRC_/Medical Research Council/United Kingdom GR - CAF/06/24/CSO_/Chief Scientist Office/United Kingdom GR - 11650/CRUK_/Cancer Research UK/United Kingdom GR - 17263/CRUK_/Cancer Research UK/United Kingdom PT - Evaluation Study PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20140409 PL - England TA - Gut JT - Gut JID - 2985108R RN - 0 (Antineoplastic Agents) RN - 0 (Biomarkers, Tumor) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Tumor Suppressor Protein p53) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.1.1 (mTOR protein, mouse) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 3.1.3.67 (PTEN Phosphohydrolase) RN - EC 3.1.3.67 (PTEN protein, human) RN - EC 3.1.3.67 (Pten protein, mouse) RN - EC 3.6.5.2 (Hras protein, mouse) RN - EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras)) RN - W36ZG6FT64 (Sirolimus) SB - IM CIN - Gut. 2014 Sep;63(9):1379-80. PMID: 24966285 MH - Animals MH - Antineoplastic Agents/*therapeutic use MH - Biomarkers, Tumor/*antagonists & inhibitors/metabolism MH - Carcinoma, Pancreatic Ductal/diagnostic imaging/*drug therapy/genetics/metabolism MH - Cell Line, Tumor MH - Drug Administration Schedule MH - Gene Expression Regulation, Neoplastic MH - Humans MH - Injections, Intraperitoneal MH - Mice MH - Mice, Mutant Strains MH - Mutation MH - PTEN Phosphohydrolase/deficiency/genetics MH - Pancreatic Neoplasms/diagnostic imaging/*drug therapy/genetics/metabolism MH - Positron-Emission Tomography MH - Protein Kinase Inhibitors/*therapeutic use MH - Proto-Oncogene Proteins p21(ras)/deficiency/genetics MH - Sirolimus/*therapeutic use MH - TOR Serine-Threonine Kinases/*antagonists & inhibitors/metabolism MH - Treatment Outcome MH - Tumor Suppressor Protein p53/deficiency/genetics PMC - PMC4145424 OTO - NOTNLM OT - Cell Signalling OT - Genetics OT - Pancreatic Cancer OT - Pharmacogenomics EDAT- 2014/04/11 06:00 MHDA- 2014/10/01 06:00 CRDT- 2014/04/11 06:00 PHST- 2014/04/11 06:00 [entrez] PHST- 2014/04/11 06:00 [pubmed] PHST- 2014/10/01 06:00 [medline] AID - gutjnl-2013-306202 [pii] AID - 10.1136/gutjnl-2013-306202 [doi] PST - ppublish SO - Gut. 2014 Sep;63(9):1481-9. doi: 10.1136/gutjnl-2013-306202. Epub 2014 Apr 9.