title: Gamma secretase inhibition promotes hypoxic necrosis in mouse pancreatic ductal adenocarcinoma.
abstract: 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.
authors.affiliation: Cancer Research UK Cambridge Research Institute, Robinson Way, Cambridge CB2 0RE, England, UK.
authors.forename: Natalie
authors.initials: N
authors.lastname: Cook
authors.forename: Kristopher K
authors.initials: KK
authors.lastname: Frese
authors.forename: Tashinga E
authors.initials: TE
authors.lastname: Bapiro
authors.forename: Michael A
authors.initials: MA
authors.lastname: Jacobetz
authors.forename: Aarthi
authors.initials: A
authors.lastname: Gopinathan
authors.forename: Jodi L
authors.initials: JL
authors.lastname: Miller
authors.forename: Sudhir S
authors.initials: SS
authors.lastname: Rao
authors.forename: Tim
authors.initials: T
authors.lastname: Demuth
authors.forename: William J
authors.initials: WJ
authors.lastname: Howat
authors.forename: Duncan I
authors.initials: DI
authors.lastname: Jodrell
authors.forename: David A
authors.initials: DA
authors.lastname: Tuveson
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003499:Cyclic S-Oxides / Q000008:administration & dosage / Q000494:pharmacology*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology; D006801:Humans; D000860:Hypoxia / Q000139:chemically induced; D051379:Mice; D008817:Mice, Mutant Strains; D009336:Necrosis; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013830:Thiadiazoles / Q000008:administration & dosage / Q000494:pharmacology*; D057170:Translational Research, Biomedical; D000093542:Gemcitabine
chemical_list: D003499:Cyclic S-Oxides; C523799:MRK 003; D011480:Protease Inhibitors; D051880:Receptors, Notch; D013830:Thiadiazoles; D003841:Deoxycytidine; D053829:Amyloid Precursor Protein Secretases; D000093542:Gemcitabine