Preclinical Development CDK-4 Inhibitor P276 Sensitizes Pancreatic Cancer Cells to

Despite advances inmolecular pathogenesis, pancreatic cancer remains amajor unsolved health problem. It is a rapidly invasive, metastatic tumor that is resistant to standard therapies. The phosphatidylinositol-3-kinase/Akt and mTOR signaling pathways are frequently dysregulated in pancreatic cancer. Gemcitabine is themainstay treatment formetastatic pancreatic cancer. P276 is a novelCDK inhibitor that inducesG2/Marrest and inhibits tumor growth in vivomodels. Here, we determined that P276 sensitizes pancreatic cancer cells to gemcitabine-induced apoptosis, a mechanism-mediated through inhibition of Akt-mTOR signaling. In vitro, the combination ofP276 andgemcitabine resulted in adose- and time-dependent inhibition ofproliferation and colony formation of pancreatic cancer cells but not with normal pancreatic ductal cells. This combination also induced apoptosis, as seen by activated caspase-3 and increased Bax/Bcl2 ratio. Gene profiling studies showed that this combination downregulated Akt-mTOR signaling pathway, which was confirmed by Western blot analyses. There was also a downregulation of VEGF and interleukin-8 expression suggesting effects on angiogenesis pathway. In vivo, intraperitoneal administration of the P276-Gem combination significantly suppressed the growth of pancreatic cancer tumor xenografts. There was a reduction in CD31-positive blood vessels and reduced VEGF expression, again suggesting an effect on angiogenesis. Taken together, these data suggest that P276-Gemcombination is a novel potent therapeutic agent that can target theAkt-mTORsignaling pathway to inhibit both tumor growth and angiogenesis. Mol Cancer Ther; 1–11. 2012 AACR