Gamma secretase inhibition promotes hypoxic necrosis in mouse pancreatic ductal adenocarcinoma

Cook, N., Frese, K. K., Bapiro, T. E., Jacobetz, M. A., Gopinathan, A., Miller, J. L., Rao, S. S., Demuth, T., Howat, W. J., Jodrell, D. I., Tuveson, D. A. (March 2012) Gamma secretase inhibition promotes hypoxic necrosis in mouse pancreatic ductal adenocarcinoma. J Exp Med, 209 (3). pp. 437-44. ISSN 1540-9538 (Electronic)0022-1007 (Linking)

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DOI: 10.1084/jem.20111923


Pancreatic ductal adenocarcinoma (PDA) is a highly lethal disease that is refractory to medical intervention. Notch pathway antagonism has been shown to prevent pancreatic preneoplasia progression in mouse models, but potential benefits in the setting of an established PDA tumor have not been established. We demonstrate that the gamma secretase inhibitor MRK003 effectively inhibits intratumoral Notch signaling in the KPC mouse model of advanced PDA. Although MRK003 monotherapy fails to extend the lifespan of KPC mice, the combination of MRK003 with the chemotherapeutic gemcitabine prolongs survival. Combination treatment kills tumor endothelial cells and synergistically promotes widespread hypoxic necrosis. These results indicate that the paucivascular nature of PDA can be exploited as a therapeutic vulnerability, and the dual targeting of the tumor endothelium and neoplastic cells by gamma secretase inhibition constitutes a rationale for clinical translation.

Item Type: Paper
Uncontrolled Keywords: Amyloid Precursor Protein Secretases/ antagonists & inhibitors Animals Anoxia/chemically induced Carcinoma, Pancreatic Ductal/blood supply/ drug therapy/metabolism/pathology Cell Line, Tumor Cell Proliferation/drug effects Cyclic S-Oxides/administration & dosage/ pharmacology Deoxycytidine/administration & dosage/analogs & derivatives Drug Synergism Drug Therapy, Combination Endothelial Cells/drug effects/pathology Humans Mice Mice, Mutant Strains Necrosis Pancreatic Neoplasms/blood supply/ drug therapy/metabolism/pathology Protease Inhibitors/administration & dosage/pharmacology Receptors, Notch/metabolism Signal Transduction/drug effects Thiadiazoles/administration & dosage/ pharmacology Translational Medical Research
Subjects: diseases & disorders > cancer > cancer types > pancreatic cancer
CSHL Authors:
Communities: CSHL labs > Tuveson lab
Depositing User: Matt Covey
Date: 12 March 2012
Date Deposited: 23 Jul 2015 15:08
Last Modified: 23 Jul 2015 15:08
PMCID: PMC3302221
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