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) (PMCID:PMC5135633)
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130578.pdf - Accepted Version 20MB |
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: | Morton, Professor Jen and Jacob, Dr Wright and Evans, Professor Jeff 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 > School 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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