Inhibition of gamma-secretase activity inhibits tumor progression in a mouse model of pancreatic ductal adenocarcinoma.
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.
Plentz
Ruben
R
Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts 02114, USA.
Park
Ji-Sun
JS
Rhim
Andrew D
AD
Abravanel
Daniel
D
Hezel
Aram F
AF
Sharma
Sreenath V
SV
Gurumurthy
Sushma
S
Deshpande
Vikram
V
Kenific
Candia
C
Settleman
Jeffrey
J
Majumder
Pradip K
PK
Stanger
Ben Z
BZ
Bardeesy
Nabeel
N
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
D003499:Cyclic S-Oxides; C523799:MRK 003; D051880:Receptors, Notch; D013830:Thiadiazoles; D053829:Amyloid Precursor Protein Secretases