作者
Chia-Yen C Wu, Eileen S Carpenter, Kenneth K Takeuchi, Christopher J Halbrook, Louise V Peverley, Harold Bien, Jason C Hall, Kathleen E DelGiorno, Debjani Pal, Yan Song, Chanjuan Shi, Richard Z Lin, Howard C Crawford
发表日期
2014/12/1
期刊
Gastroenterology
卷号
147
期号
6
页码范围
1405-1416. e7
出版商
WB Saunders
简介
Background & Aims
New drug targets are urgently needed for the treatment of patients with pancreatic ductal adenocarcinoma (PDA). Nearly all PDAs contain oncogenic mutations in the KRAS gene. Pharmacological inhibition of KRAS has been unsuccessful, leading to a focus on downstream effectors that are more easily targeted with small molecule inhibitors. We investigated the contributions of phosphoinositide 3-kinase (PI3K) to KRAS-initiated tumorigenesis.
Methods
Tumorigenesis was measured in the KrasG12D/+;Ptf1aCre/+ mouse model of PDA; these mice were crossed with mice with pancreas-specific disruption of genes encoding PI3K p110α (Pik3ca), p110β (Pik3cb), or RAC1 (Rac1). Pancreatitis was induced with 5 daily intraperitoneal injections of cerulein. Pancreata and primary acinar cells were isolated; acinar cells were incubated with an inhibitor of p110α (PIK75) followed by a broad-spectrum …
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