mTORC2 signaling drives the development and progression of pancreatic cancer

Driscoll, D. R. et al. (2016) mTORC2 signaling drives the development and progression of pancreatic cancer. Cancer Research, 76(23), pp. 6911-6923. (doi:10.1158/0008-5472.CAN-16-0810) (PMID:27758884)

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Abstract

mTOR signaling controls several critical cellular functions and is deregulated in many cancers, including pancreatic cancer. To date, most efforts have focused on inhibiting the mTORC1 complex. However, clinical trials of mTORC1 inhibitors in pancreatic cancer have failed, raising questions about this therapeutic approach. We employed a genetic approach to delete the obligate mTORC2 subunit Rictor and identified the critical times during which tumorigenesis requires mTORC2 signaling. Rictor deletion resulted in profoundly delayed tumorigenesis. Whereas previous studies showed most pancreatic tumors were insensitive to rapamycin, treatment with a dual mTORC1/2 inhibitor strongly suppressed tumorigenesis. In late-stage tumor-bearing mice, combined mTORC1/2 and PI3K inhibition significantly increased survival. Thus, targeting mTOR may be a potential therapeutic strategy in pancreatic cancer.

Item Type:Articles
Additional Information:This work was funded by CRUK (C596/A18076, C596/A17196) and NIH grants R01CA155784 to B.C. Lewis and F30CA168063 to B.J. Quattrochi.
Keywords:pancreatic cancer, mTORC2.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Jacob, Dr Wright and Morton, Dr Jennifer and Evans, Professor Thomas and Karim, Ms Saadia and Sansom, Professor Owen
Authors: Driscoll, D. R., Karim, S. A., Sano, M., Gay, D. M., Jacob, W., Yu, J., Mizukami, Y., Gopinathan, A., Jodrell, D. I., Evans, T.R. J., Bardeesy, N., Hall, M. N., Quattrochi, B. J., Klimstra, D. S., Barry, S. T., Sansom, O. J., Lewis, B. C., and Morton, J. P.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Cancer Research
Journal Abbr.:Cancer Res
Publisher:American Association for Cancer Research
ISSN:0008-5472
ISSN (Online):1538-7445
Published Online:06 October 2016
Copyright Holders:Copyright © 2016 American Association for Cancer Research
First Published:First published in Cancer Research 76(23):6911-6923
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
647981CR-UK Centre renewalKaren VousdenCancer Research UK (CAN-RES-UK)C596/A18076RI CANCER SCIENCES