title: mTORC2 Signaling Drives the Development and Progression of Pancreatic Cancer.
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.
authors.affiliation: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts.
authors.forename: David R
authors.initials: DR
authors.lastname: Driscoll
authors.affiliation: CRUK Beatson Institute, Glasgow, United Kingdom.
authors.forename: Saadia A
authors.initials: SA
authors.lastname: Karim
authors.affiliation: Department of Pathology and Microbiology, Nihon University School of Medicine, Tokyo, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Sano
authors.affiliation: CRUK Beatson Institute, Glasgow, United Kingdom.
authors.forename: David M
authors.initials: DM
authors.lastname: Gay
authors.affiliation: Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Wright
authors.initials: W
authors.lastname: Jacob
authors.affiliation: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts.
authors.forename: Jun
authors.initials: J
authors.lastname: Yu
authors.affiliation: Cancer Center, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Mizukami
authors.affiliation: CRUK Cambridge Institute, Cambridge, United Kingdom.
authors.forename: Aarthi
authors.initials: A
authors.lastname: Gopinathan
authors.affiliation: CRUK Cambridge Institute, Cambridge, United Kingdom.
authors.forename: Duncan I
authors.initials: DI
authors.lastname: Jodrell
authors.affiliation: CRUK Beatson Institute, Glasgow, United Kingdom.|Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: T R Jeffry
authors.initials: TR
authors.lastname: Evans
authors.affiliation: Cancer Center, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Nabeel
authors.initials: N
authors.lastname: Bardeesy
authors.affiliation: Biozentrum, University of Basel, Basel, Switzerland.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Hall
authors.affiliation: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Quattrochi
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: David S
authors.initials: DS
authors.lastname: Klimstra
authors.affiliation: AstraZeneca, Macclesfield, United Kingdom.
authors.forename: Simon T
authors.initials: ST
authors.lastname: Barry
authors.affiliation: CRUK Beatson Institute, Glasgow, United Kingdom. o.sansom@beatson.gla.ac.uk Brian.Lewis@umassmed.edu.|Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Owen J
authors.initials: OJ
authors.lastname: Sansom
authors.affiliation: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts. o.sansom@beatson.gla.ac.uk Brian.Lewis@umassmed.edu.|Cancer Center, University of Massachusetts Medical School, Worcester, Massachusetts.
authors.forename: Brian C
authors.initials: BC
authors.lastname: Lewis
authors.affiliation: CRUK Beatson Institute, Glasgow, United Kingdom.|Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Jennifer P
authors.initials: JP
authors.lastname: Morton
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D018450:Disease Progression; D006801:Humans; D051379:Mice; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics*
chemical_list: C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases