Targeting mTOR dependency in pancreatic cancer.
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.


METHODS
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.
CRUK Beatson Institute, Glasgow, UK.
Douglas C
DC
Morran
The Kinghorn Cancer Centre and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia.
Jianmin
J
Wu
West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK.
Nigel B
NB
Jamieson
CRUK Beatson Institute, Glasgow, UK.
Agata
A
Mrowinska
CRUK Beatson Institute, Glasgow, UK.
Gabriela
G
Kalna
CRUK Beatson Institute, Glasgow, UK.
Saadia A
SA
Karim
CRUK Beatson Institute, Glasgow, UK.
Amy Y M
AY
Au
School of Environmental & Life Sciences, University of Newcastle, Ourimbah, New South Wales, Australia.
Christopher J
CJ
Scarlett
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.
David K
DK
Chang
CRUK Beatson Institute, Glasgow, UK.
Malgorzata Z
MZ
Pajak
CRUK Beatson Institute, Glasgow, UK Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
Karin A
KA
Oien
West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK.
Colin J
CJ
McKay
West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK.
C Ross
CR
Carter
West of Scotland PET Centre, Gartnavel General Hospital, Glasgow, UK.
Gerry
G
Gillen
West of Scotland Radionuclide Dispensary, NHS Greater Glasgow and Clyde, Glasgow, UK.
Sue
S
Champion
West of Scotland Radionuclide Dispensary, NHS Greater Glasgow and Clyde, Glasgow, UK.
Sally L
SL
Pimlott
CRUK Beatson Institute, Glasgow, UK.
Kurt I
KI
Anderson
CRUK Beatson Institute, Glasgow, UK Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
T R Jeffry
TR
Evans
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.
Sean M
SM
Grimmond
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.
Andrew V
AV
Biankin
CRUK Beatson Institute, Glasgow, UK.
Owen J
OJ
Sansom
CRUK Beatson Institute, Glasgow, UK.
Jennifer P
JP
Morton
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D021441:Carcinoma, Pancreatic Ductal / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004334:Drug Administration Schedule; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007274:Injections, Intraperitoneal; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D049268:Positron-Emission Tomography; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D016283:Proto-Oncogene Proteins p21(ras) / Q000172:deficiency / Q000235:genetics; D020123:Sirolimus / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D047428:Protein Kinase Inhibitors; D016159:Tumor Suppressor Protein p53; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C487757:Pten protein, mouse; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras); D020123:Sirolimus
Cell Signalling; Genetics; Pancreatic Cancer; Pharmacogenomics