Mutant Pik3ca-Mediated Pancreatic Tumorigenesis And The Response To Pi3k Pathway Inhibition.

e15273 Background: Pancreatic ductal adenocarcinoma (PDA) remains a leading cause of cancer related mortality despite recent treatment advances. The majority of PDAs are initiated secondary to KRAS mutations, which result in resistance to targeted therapies. Subsets of pancreatic cancers possess PIK3CA mutations, which lead to oncogenic activation of the PI3K pathway. Here we examined the ability of PIK3CA mutations to initiate pancreatic tumorigenesis and the response of PIK3CA-mutant PDAs to dual PI3K/mTOR inhibition. Methods: Genetically engineered murine models were generated expressing a constitutively active PI3K within the pancreas, including the PIK3CA H1047R hotspot mutation. A time course was examined to understand tumorigenesis in these models. Mice with PIK3CA mutant pancreatic cancer were treated with a dual PI3K/mTOR inhibitor, NVP-BEZ235 (35mg/kg body weight/day dissolved in 1 volume N-methyl-2-pyrrolidone and 9 volumes PEG300), or a vehicle-only control. Results: A constitutively active PI...