title: Inhibition of gamma-secretase activity inhibits tumor progression in a mouse model of pancreatic ductal adenocarcinoma.
abstract: OBJECTIVE
  The Notch signaling pathway is required for the expansion of undifferentiated pancreatic progenitor cells during embryonic development and has been implicated in the progression of pancreatic ductal adenocarcinoma (PDAC). The interaction of Notch ligands with their receptors promotes a gamma-secretase-dependent cleavage of the Notch receptor and release of the Notch intracellular domain, which translocates to the nucleus and activates transcription. We investigated the role of this pathway in PDAC progression.
  
  
  METHODS
  We tested the effects of a gamma-secretase inhibitor (GSI) that blocks Notch signaling in PDAC cell lines and a genetically engineered mouse model of PDAC (Kras p53 L/+ mice).
  
  
  RESULTS
  Notch signaling was activated in PDAC precursors and advanced tumors. The GSI inhibited the growth of premalignant pancreatic duct-derived cells in a Notch-dependent manner. Additionally, in a panel of over 400 human solid tumor-derived cell lines, PDAC cells, as a group, were more sensitive to the GSI than any other tumor type. Finally, the GSI completely inhibited tumor development in the genetically engineered model of invasive PDAC (P < .005, chi2 test; compared with mice exposed to vehicle).
  
  
  CONCLUSIONS
  These results suggest that Notch signaling is required for PDAC progression. Pharmacologic targeting of this pathway offers therapeutic potential in this treatment-refractory malignancy.
authors.affiliation: Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: Ruben
authors.initials: R
authors.lastname: Plentz
authors.forename: Ji-Sun
authors.initials: JS
authors.lastname: Park
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Rhim
authors.forename: Daniel
authors.initials: D
authors.lastname: Abravanel
authors.forename: Aram F
authors.initials: AF
authors.lastname: Hezel
authors.forename: Sreenath V
authors.initials: SV
authors.lastname: Sharma
authors.forename: Sushma
authors.initials: S
authors.lastname: Gurumurthy
authors.forename: Vikram
authors.initials: V
authors.lastname: Deshpande
authors.forename: Candia
authors.initials: C
authors.lastname: Kenific
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Settleman
authors.forename: Pradip K
authors.initials: PK
authors.lastname: Majumder
authors.forename: Ben Z
authors.initials: BZ
authors.lastname: Stanger
authors.forename: Nabeel
authors.initials: N
authors.lastname: Bardeesy
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002460:Cell Line; D045744:Cell Line, Tumor; D003499:Cyclic S-Oxides / Q000494:pharmacology; D018450:Disease Progression; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D051880:Receptors, Notch / Q000502:physiology*; D015398:Signal Transduction; D013830:Thiadiazoles / Q000494:pharmacology
chemical_list: D003499:Cyclic S-Oxides; C523799:MRK 003; D051880:Receptors, Notch; D013830:Thiadiazoles; D053829:Amyloid Precursor Protein Secretases