Der Smoothened-Antagonist LDE225 hemmt die Proliferation in Gemcitabin-sensitiven und -resistenten Zelllinien des duktalen Adenokarzinoms des Pankreas

The treatment of the ductal adenocarcinoma oft the pancreas (PDAC) is one of the least successful of all cancers, causing it to range amongst the cancer diseases with the grimmest prognosis. This is partly due to quickly emerging chemoresistance of the PDAC against Gemcitabine, the current standard of treatment. In recent years, hedgehog (Hh) inhibitors have shown promising results in in vitro-trials and mice xenografts, resulting in further testing of several substances in clinical trials that are currently underway. LDE225 is a low-molecular antagonist of Smoothened (SMO) and has already been used in several publications on pancreatic cancer. In the present thesis, we investigated the effect of SMO inhibition with LDE225 on the tumor cell lines Capan-1 and Panc-1. One particular question in mind was how chemoresistance would have an impact on the efficacy of the treatment with a SMO inhibitor. We used both commercially available wildtype (wt) cell lines which are sensitive against Gemcitabine, and Gemcitabine-resistant (GR) cell lines which were bred in our laboratory. It was shown that sufficient dosing of LDE225 is inhibiting proliferation in all cell lines used. Acquired chemoresistance resulted in altered efficacy of LDE225 compared to wt cells. SMO inhibition did not increase sensitivity against Gemcitabine in GR cells. Use of LDE225 did not lead to an increase of apoptosis, but we could observe a shift in the G1 fraction. Gene expression analysis was conducted to describe mechanisms of Hh pathway modification after SMO inhibition in the cell lines used. Numerous publications have dealt with the effects of Hh inhibitors on tumorous stroma or cancer stem cells. The present thesis is explicitly focused on the treatment of the tumor cells with a low-molecular SMO antagonist and displays feedback mechanisms between acquired chemoresistance and Hh activity of the PDAC. It aims to gain insight to a complex topic that has not yet been thoroughly investigated.