title: Combined inhibition of Notch and JAK/STAT is superior to monotherapies and impairs pancreatic cancer progression.
abstract: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a high rate of metastasis. Recent studies have indicated that Notch and janus kinase 2 (JAK2)/signal transducers and activators of transcription 3 (STAT3) signaling pathways are both important for the initiation and progression of PDAC. The purpose of this study was to determine the outcome of targeting these two tumor signaling pathways simultaneously both in vitro and in vivo. We assessed the combinational effects of the γ-secretase inhibitor IX (GSI IX) and JAK2 inhibitor (AG-490) on growth and epithelial plasticity of human pancreatic cancer cell lines, and in a genetically engineered mouse model (Pdx1-Cre, LSL-KrasG12D, p53(lox/+)) of PDAC. Dual treatment with GSI IX and AG-490 significantly impaired cell proliferation, migration, invasion, soft agar growth and apoptosis when compared with monotherapies. Most importantly, combinational treatment significantly attenuates tumor progression in vivo and suppresses conversion from acinar-ductal-metaplasia to PDAC. Our results suggest that targeting Notch and JAK2/STAT3 signaling pathways simultaneously is superior to single inhibitions, supporting combined treatment by GSI IX and AG-490 as a potential therapeutic approach for PDAC. However, the study design limits the direct transfer into the clinic and the impact of dual treatment in patients with PDAC remains still to be determined.
authors.affiliation: Department of Internal Medicine I, Medical University Hospital, 72076 Tuebingen , Germany.
authors.forename: Vindhya
authors.initials: V
authors.lastname: Palagani
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Bozko
authors.forename: Mona
authors.initials: M
authors.lastname: El Khatib
authors.forename: Hanane
authors.initials: H
authors.lastname: Belahmer
authors.forename: Nathalia
authors.initials: N
authors.lastname: Giese
authors.forename: Bence
authors.initials: B
authors.lastname: Sipos
authors.forename: Nisar P
authors.initials: NP
authors.lastname: Malek
authors.forename: Ruben R
authors.initials: RR
authors.lastname: Plentz
mesh_terms: D045744:Cell Line, Tumor; D018450:Disease Progression; D006801:Humans; D009369:Neoplasms / Q000473:pathology*; D011494:Protein Kinases / Q000378:metabolism*; D051880:Receptors, Notch / Q000037:antagonists & inhibitors*; D050791:STAT Transcription Factors / Q000037:antagonists & inhibitors*
chemical_list: D051880:Receptors, Notch; D050791:STAT Transcription Factors; D011494:Protein Kinases