Platinum compounds remain the cornerstone for both early and advanced stages NSCLC management. However, mechanisms underlying platinum resistance and sensitivity are poorly understood, and no major impact in patient selection or treatment modulation has been achieved to date. Apoptosis inhibition and platinum-efflux are potential mechanisms, therefore we evaluated the role of XIAP, pAkt, and ATP7A in this setting. We have analyzed the tumor cell lines, LC94, LC319, and A549, all of adenocarcinoma histology and harboring KRAS mutations. The cisplatin (CPT) IC50 was assessed using MTT assay, after 48 h incubation. mRNA expression was evaluated by Real-time PCR, while Western blotting was performed to analyze protein expression. Also, two distinct cohorts of NSCLC patients were evaluated. The first was comprised of 39 patients diagnosed as early-stage NSCLC (IA-IIIB), whereas the second included patients with metastatic disease (IV). In the latter, patients were clinically classified as platinum-sensitive (N=4) and platinum-non-sensitive group (N=47). We have analyzed either mRNA expression or protein expression. NSCLC cell lines exhibited distinct profiles of CPT sensitivity. LC94 was especially sensitive to CPT, in contrast to LC319 and A549. Resistant cell lines (LC319 and A549) showed a positive correlation between high XIAP and ATP7A mRNA expression when compared to LC94. These data was corroborated by XIAP and ATP7A mRNA expression, which also showed a significant positive correlation (R2=0,88) in early-diagnosed patients (IA-IIIB). we did not correlate these data to response to CPT, since only few patients of this cohort received adjuvant therapy. XIAP protein expression was evaluated in cell lines and in the second clinical cohort. In fact, XIAP showed a considerably higher expression in LC 319 and A549 than in LC 94. Interestingly, XIAP shRNA lead not only to XIAP downregulation (85% reduction in mRNA compared to empty-vector control), but also to ATP7A (60% of reduction in mRNA). These changes were accompanied by reduction in the respective protein levels. Among patients with metastatic NSCLC, XIAP was expressed in 45% (21/47) in the platinum-non-sensitive group, while no expression was observed in the sensitive (0/4). Knowing that XIAP is regulated by PI3K/Akt pathway through phosphorylation at the serine 87 residue, which increases XIAP stability and accumulation, we further analyzed the Akt phosphorylation. LC319 displayed superior Akt phosporylation, in comparison to the lower level in LC 94. XIAP, pAkt, and ATP7A mRNA expression were positively correlated to CPT resistance/sensitivity in NSCLC. Furthermore, XIAP seems to indirectly regulate ATP7A transcritption and the correlation of expression of both proteins might cooperate for NSCLC chemoresistance. Further analyses are warranted to validate these findings and explore their potential as biomarkers in this setting. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1731. doi:1538-7445.AM2012-1731