What tumor cells cannot resist Mechanisms of therapy resistance in esophageal adenocarcinoma

The incidence of esophageal adenocarcinoma (EAC) has increased six-fold during the last three decades, with approximately 2.500 newly diagnosed patients each year in the Netherlands. Depending on tumor stage, patients face a poor 5-year survival of 5-40% despite the benefits of recent multimodality treatment options. This is mainly due to the activation of efficient therapy resistance mechanisms and aggressive tumor behavior leading to early onset of metastatic disease. The results described in this thesis show that EAC cells are able to activate various mechanisms of resistance, following therapeutic pressure, making it challenging to treat EAC patients in a uniformly effective manner. Furthermore, limited treatment options are currently available for the treatment of EAC, which contributes to the poor overall survival of these patients. In this thesis we unraveled mechanisms of therapy resistance and identified biomarkers, hopefully enabling the development of more effective treatment options and may contribute to patient stratification. Especially the identification of therapy induced Epithelial-to-Mesenchymal Transition (EMT) is likely to open new avenues for treatment of EAC patients. The development of in vitro and in vivo EAC models, such as the patient-derived xenografts and novel primary organoid cultures described in this thesis provide excellent tools to further unravel mechanisms of drug resistance. Taken together, the new findings described in this thesis can guide the development of new anticancer treatment strategies directed against EAC and are -due to availability of FDA approved drugs for most of the targets identified- ready to be used in clinical trials.