Dual inhibition of Notch and JAK/STAT impairs pancreatic cancer progression in vitro and in vivo and is superior to monotherapies

Background and aims: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a high rate of metastasis. Recent studies have indicated that Notch and JAK2/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.

Methods: We assessed the combinational effects of the gamma-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.

Results: Dual treatment with GSI IX and AG-490 significantly impaired cell proliferation, migration, invasion, soft agar growth and apoptosis when compared to monotherapies. Notably, inhibition of Hes1 down regulated phosphorylation of STAT3 and reflects a synergistic effect. Most importantly, combinational treatment significantly attenuates tumor progression in vivo and suppresses conversion from acinar-ductal-metaplasia (ADM) to PDAC.

Conclusions: Our results suggest that targeting Notch and JAK2/STAT3 signaling pathways simultaneously is superior to single inhibitions, supporting combined treatment by GSI X and AG-490 as a potential therapeutic approach for PDAC.