MTORC2 Signaling Drives the Development and Progression of Pancreatic Cancer

Overview

Journal Cancer Res

Specialty Oncology

Date 2016 Oct 21

PMID 27758884

Citations 46

Authors

David R Driscoll

Saadia A Karim

Makoto Sano

David M Gay

Wright Jacob

Jun Yu

Yusuke Mizukami

Aarthi Gopinathan

Duncan I Jodrell

T R Jeffry Evans

Nabeel Bardeesy

Michael N Hall

Brian J Quattrochi

David S Klimstra

Simon T Barry

Owen J Sansom

Brian C Lewis

Jennifer P Morton

Affiliations

Soon will be listed here.

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. Cancer Res; 76(23); 6911-23. ©2016 AACR.

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