e19123 Background: Molecular mechanisms of drug-resistance remain still unclear; it is believed multifactorial, involving host factors, numerous molecular events as well as genetic and epigenetic changes. We were aimed to use massive expression assays before and after epigenetic treatment to explore predictors for platinum and radiation therapy in NSCLC. Methods: By using an expression microarray analysis, we looked for those genes reactivated in a set of two cisplatin (CDDP) resistant and sensitive NSCLC cell lines after epigenetic treatment. Gene expression, promoter methylation and CDDP-chemoresponse were further analyzed in three matched sets of sensitive/resistant cell lines, 23 human cancer cell lines and 36 NSCLC specimens. Then, to investigate the importance of methylation in radiosensitivity, we have developed radiation clonogenic cell survival assays with three paired Sensitive/CDDP-Resistant cell lines that present a different gene expression and promoter methylation profile. Finally, we have explored in vitro data into three cohorts of patients from different institutions that were treated with radio, chemoradiation or chemotherapy alone. Results: IGF-1/IGFBP3 axis was significantly associated with response to therapy and promoter methylation of IGFBP3 was critical to predict biological behavior. In this regard, hypermethylated and semimethylated cell lines presented a higher sensitivity to radiotherapy and cisplatin than cell lines completely unmethylated for IGFBP3 promoter. However, when resistance to cisplatin treatment was not mediated by IGFBP3 promoter methylation there were also not significant changes regarding sensitivity to radiotherapy treatment. Finally, in vitro data for IGF-1/IGFBP3 axis were confirmed in three cohorts of patients. Conclusions: IGF-1/IGFBP3 axis plays a central role in resistance to chemo- and radiation therapy in NSCLC patients.