Pancreatic cancer is the fourth leading cause of cancer death, with an overall 5-year survival rate of <10%. These statistics have not changed in almost 50 years. Chemotherapy-resistance is a major barrier for successful therapy of pancreatic duct adeno carcinoma (PDAC). Resistance may arise de novo or is acquired upon intensified chemotherapeutic regimens. Hence, a better characterization of the underlying mechanisms and the identification of new drug targets are a therapeutic necessity.
Primary pancreatic cancer cells were isolated from CKP (Ptf1a+/Cre, Kras+/LSL-G12D, P53loxP/loxP) mouse and cultured with increasing concentrations of gemcitabine to induce gemcitabine-resistant cell lines. The resistance status was determined by dose-response experiments, calculating the half maximal inhibitory concentration (IC50) of gemcitabine using cell titer assays. Alterations in the Pi3k-akt pathway were identified by genome-wide analyses and verified by Western blot.
Our data indicate that the pi3k-akt pathway is over-activated in gemcitabine-resistant cells. Accordingly, the gemcitabine-resistant cells were more sensitive to pi3k inhibitors than gemcitabine-naïve cells cultured in parallel. Besides the pi3k pathway, several key genes controlling energy metabolism and proliferation were also significantly altered in the gemcitabine-resistant cells as compared with controls.
Gemcitabine treatment might have unwanted side effects by triggering the pi3k-akt pathway in treatment-induced resistance. In order to prevent or overcome this development, a parallel application of pi3k-akt inhibitors along or subsequent to gemcitabine plus abraxane may constitute a meaningful adjuvant treatment strategy. This hypothesis needs to be tested in further detail.