Preclinical strategies targeted at non-small-cell lung cancer signalling pathways with striking translational fallout

► Improvement of NSCLC patients outcome with conventional cytotoxic agents is poor. ► Many processes involved in NSCLC development and genetic aetiology have been defined. ► EGFR and c-MetR mutants in NSCLC are intriguing targets for specific inhibitors. ► Drug resistance might be overcome targeting Cancer-Initiating Cells. ► Combination of targeted and standard therapies is promising in NSCLC management.