ATF2 is a transcription factor involved in stress and DNA damage. A correlation between ATF2 JNK-mediated activation and resistance to damaging agents has already been reported. The purpose of the present study was to investigate whether ATF2 may have a role in acquired resistance to cisplatin in Non-Small-Cell-Lung-Cancer (NSCLC). mRNA and protein analysis on matched cancer and corresponding normal tissues from surgically resected NSCLC have been performed. Furthermore, in NSCLC cell lines ATF2 expression levels were evaluated and correlated to Platinum (CDDP) resistance. Celastrol mediated ATF2/cJUN activity was measured. High expression levels of both ATF2 transcript and proteins were observed in lung cancer specimens (p≪0.01, Log2(FC)=+4.7). CDDP resistant NSCLC cell lines expressed high levels of ATF2 protein. By contrast, Celastrol mediated ATF2/cJUN functional inhibition restored the response to CDDP. Moreover, ATF2 protein activation correlates with worse outcome in advanced CDDP-treated patients. For the first time it has been shown NSCLC ATF2 up-regulation at both mRNA/protein levels. In addition, we reported that in NSCLC cell lines a correlation between ATF2 protein expression and CDDP resistance occurs. Altogether, our results indicate a potential increase in CDDP sensitivity, upon Celastrol-mediated ATF2/cJUN inhibition. This data suggest a possible involvement of ATF2 in NSCLC CDDP-resistance. © 2014 Wiley Periodicals, Inc.