Targeting mTOR dependency in pancreatic cancer

Morran, Douglas C., Wu, Jianmin, Jamieson, Nigel B., Mrowinska, Agata, Kalna, Gabriela, Karim, Saadia, A., Au, Amy Y. M., Scarlett, Christopher J., Chang, David K., Pajak, Malgorzata Z., Australian Pancreatic Cancer Genome Initiative (APGI), Oien, Karin A., McKay, Colin J., Carter, C. Ross, Gillen, Gerry, Champion, Sue, Pilmott, Sally L., Anderson, Kurt I., Evans, T. R. Jeffry, Grimmond, Sean M., Biankin, Andrew V., Sansom, Owen J. and Morton, Jennifer P. (2014) Targeting mTOR dependency in pancreatic cancer. Gut, 63 9: 1481-1489. doi:10.1136/gutjnl-2013-306202

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Author Morran, Douglas C.
Wu, Jianmin
Jamieson, Nigel B.
Mrowinska, Agata
Kalna, Gabriela
Karim, Saadia, A.
Au, Amy Y. M.
Scarlett, Christopher J.
Chang, David K.
Pajak, Malgorzata Z.
Australian Pancreatic Cancer Genome Initiative (APGI)
Oien, Karin A.
McKay, Colin J.
Carter, C. Ross
Gillen, Gerry
Champion, Sue
Pilmott, Sally L.
Anderson, Kurt I.
Evans, T. R. Jeffry
Grimmond, Sean M.
Biankin, Andrew V.
Sansom, Owen J.
Morton, Jennifer P.
Title Targeting mTOR dependency in pancreatic cancer
Journal name Gut   Check publisher's open access policy
ISSN 0017-5749
1468-3288
Publication date 2014-04-19
Sub-type Article (original research)
DOI 10.1136/gutjnl-2013-306202
Open Access Status DOI
Volume 63
Issue 9
Start page 1481
End page 1489
Total pages 9
Place of publication London, United Kingdom
Publisher B M J Group
Language eng
Abstract 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.
Formatted 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.

What is already known on this subject?
▸ Pancreatic cancer is one of the leading causes of cancer death. Most therapies are largely ineffective and new therapies are required.
▸ Pancreatic cancer is nearly always driven by KRAS mutation, with progression driven by mutations in other genes, notably CDKN2A, TP53 and DPC4. The disease is very complex genetically, however, and many more genes are mutated at low frequencies.
▸ There may be pathways that, although deregulated relatively rarely, are key to driving specific tumours.

What are the new findings?
▸ Mammalian target of rapamycin (mTOR) inhibition can lead to proliferative arrest and even tumour regression in pancreatic tumours driven by activated KRAS and PTEN deficiency, but not in tumours driven by activated KRAS and mutant p53.
▸ Therapeutic response to mTOR inhibition can be assessed using clinically applicable positron emission tomography imaging.
▸ ∼ 20% human pancreatic tumours exhibit low PTEN expression, and a gene expression signature that overlaps with murine KRAS PTEN tumours.

How might it impact on clinical practice in the foreseeable future?
▸ This study is important as it is the first to show efficacy of a targeted therapy in a preclinical model of pancreatic cancer using the genotype-to-phenotype approach.
▸ Targeted anti-mTOR therapies may offer clinical benefit in subsets of human pancreatic ductal adenocarcinoma, selected based on genotype that are dependent on mTOR signalling.
▸ The genetic signatures of human tumours could be used to direct personalised pancreatic cancer treatment in the future.
Keyword Cell Signalling
Genetics
Pancreatic Cancer
Pharmacogenomics
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID 11650
CAF/06/24
Institutional Status UQ
Additional Notes Published Online First 9 April 2014

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
Institute for Molecular Bioscience - Publications
 
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Created: Thu, 22 May 2014, 01:57:02 EST by Susan Allen on behalf of Institute for Molecular Bioscience