Lung cancer is the most common cancer fatality in Europe (335000 deaths/yr). Non-small cell lung cancer (NSCLC) consists 85% of the cases, with 5 yr survival <15%. Hence, this proposal focuses on the urgent need for better NSCLC therapies. This is a European problem at societal and scientific level: better therapies are needed to keep the spiralling costs of European health systems under control, and the required expertise (basic science, clinical, biotech, experimental therapeutics) is scattered over the EU. Because of the diversity of the NSCLC problem (and the small/medium size of the project) we are focusing on two particular problems: 1) to find solutions for the currently clinically observed resistance problems with epidermal growth factor receptor (EGFR) targeting therapies (10% of NSCLC patients), and 2) to find a solution for the clinically unmet need for NSCLC patients with KRAS mutations (30% of NSCLC), for whom there virtually is no cure (besides very modest effects of platinum based therapies). Based on this focus, we assembled an EU wide consortium which joins excellent expertise at both the basic science (EGFR family, KRAS), clinical (involvement of several clinical study leaders) and biotech level (involvement of academic and SME biotech component). We aim:1) To identify novel drug targets for the improvement of EGFR targeting therapies and for the development of therapies for K-Ras mutant patients (via genome wide RNAi screening and kinome/secretome profiling).2) To validate these targets in innovative mouse models that replicate the clinical problem, and in patient materials (tissue and serum)3) To develop novel therapeutics based on the unique expertise of our partners: anti-receptor DARPins (designed ankyrin repeat proteins), monoclonals or soluble receptors targeting the BROADER EGFR family (to block compensatory signalling), and protein kinase inhibitorsThe results will have important basic scientific, clinical and economic impact