We have studied, in the lung adenocarcinomas bearing EGFR or KRAS mutations, TP53/p14arf status, and in the non-small cell lung cancer the contribution of Neurotensin system (NTS/NTSR1) on the tumoral progression and survival. In a series of 96 patients, TP53, KRAS and EGFR mutations were detected in 45.2 %, 15.8 % and 34.4 % of the cases, respectively. The p14arf decrease expression was observed in 57.1 % of the cases. The p53/p14arf deficit was observed in 83.3 % and 76.9% of EGFR and KRAS mutated tumors, respectively. Our results showed that the inactivation of the p53/p14arf pathway is common but not systematic in EGFR or KRAS mutated lung adenocarcinomas. Labeling of NTS and NTSR1 was found in 60.4 % of stage I (n = 139), 47% of stage II (n = 74), and 50% of stage III (n = 133) adenocarcinomas. In univariate and multivariate analysis, NTSR1 expression were significantly associated with a poor prognosis in terms of overall survival (p = 0.0081 for stage I, p = 0.0087 for stage II-III). In vivo and in vitro studies have shown that the complex NTS/NTSR1 promotes tumor progression by increasing HER2 and HER3 expression and EGFR, HER3 and HER2 activation. This latter was mediated by MMP1 activation and HB-EGF and NRG1 released. This work supports the hypothesis that complex NTS/NTSR1 actively contributes to the aggressiveness and bronchial tumor progression
