<p>The clinical management of locally advanced oesophageal adenocarcinoma (OAC) involves neoadjuvant chemoradiotherapy (CRT), but as radio resistance remains a major clinical challenge, complete pathological response to CRT only occurs in 20–30% of patients. In this study we used an established isogenic cell line model of radioresistant OAC to detect proteomic signatures of radio resistance to identify novel molecular and cellular targets of radio resistance in OAC. A total of 5785 proteins were identified of which 251 were significantly modulated in OE33R cells, when compared to OE33P. Gene ontology and pathway analysis of these significantly modulated proteins demonstrated altered metabolism in radioresistant cells accompanied by an inhibition of apoptosis. In addition, inflammatory and angiogenic pathways were positively regulated in radioresistant cells compared to the radiosensitive cells. In this study, we demonstrate, for the first time, a comprehensive proteomic profile of the established isogenic cell line model of radioresistant OAC. This analysis provides insights into the molecular and cellular pathways which regulate radio resistance in OAC. Furthermore, it identifies pathway specific signatures of radio resistance that will direct studies on the development of targeted therapies and personalised approaches to radiotherapy.</p>