Development of a novel PIK3CA-mutated pancreatic tumor mouse model and evaluation of the therapeutic effects of a PI3K inhibitor.

Pancreatic ductal adenocarcinoma (PDAC) is a fatal malignancy. Personalized medicine based on genetic mutations is required to improve its prognosis. The PI3K/AKT pathway plays a crucial role in cancer progression. While PI3K inhibitors have been developed for several malignancies, none have been clinically applied to PDAC. PIK3CA encodes the catalytic subunit of Class IA PI3K, and an activating mutation such as E545K and H1047R is oncogenic. In this study, we developed a novel pancreatic cancer mouse model with PIK3CAH1047R mutation, designated Ptf1acre/+; Rosa26-LSL-PIK3CAH1047R:p53loxP/loxP (PPC) mice. At 150 days of age, PPC mice developed PDAC and AKT was activated in their tumor epithelial cells. We established a pancreatic cancer cell line from PPC mice, and alpelisib, an inhibitor of PI3K p110α, inhibited the proliferation of PPC cells in vitro. Furthermore, PPC cells were subcutaneously transplanted into NOD/SCID mice, and alpelisib significantly reduced the tumor burden of PPC cells. Western blotting upon treatment with alpelisib revealed compensatory activation of ERK in PPC cells. Combination treatment with alpelisib and the MEK inhibitor PD98059 significantly inhibited cell proliferation. These data indicate that PIK3CA mutation may be oncogenic in PDAC and that PI3K inhibitors can be effective against such tumors. Dual inhibition of the PI3K/AKT and MEK/ERK pathways may enhance therapeutic effects in PI3K/AKT-activated pancreatic tumors.