Inhibition of the Phosphatidylinositol 3′-Kinase-AKT Pathway Induces Apoptosis in Pancreatic Carcinoma Cells in Vitro and in Vivo

The phosphatidylinositol 3′-kinase (PI3k)-AKT survival pathway is activated in many malignancies. We observed constitutive AKT phosphorylation (on S473) consistent with pathway activation in seven of nine human pancreatic carcinoma cell lines in vitro . Exposure of the cells to two structurally distinct inhibitors of PI3k (wortmannin and LY294002) resulted in a dose-dependent induction of apoptosis in six of seven of the cell lines that displayed constitutive AKT phosphorylation but not in either of the cell lines that did not. The mitogen-activated protein/extracellular signal-regulated kinase kinase-mitogen-activated protein kinase inhibitor PD98059 also induced apoptosis in two of the cell lines, including one of the LY294002-insensitive lines (AsPC-1). Exposure of orthotopic L3.6pl pancreatic tumors to LY294002 resulted in dose-dependent inhibition of tumor growth, and decreased peritoneal and liver metastases, effects that were associated with an inhibition of AKT phosphorylation and increased terminal deoxynucleotidyl transferase-mediated nick end labeling staining characteristic of apoptosis. Furthermore, a suboptimal dose of LY294002 (25 mg/kg) produced additive inhibition of tumor growth when combined with a suboptimal dose of gemcitabine (62 mg/kg). Together, our results establish that the PI3k/AKT pathway is constitutively activated in a majority of human pancreatic cancer cell lines and establish that the pathway is a promising target for therapeutic intervention.