Background: Lung cancer is the leading cause of cancer deaths in the US, with as many as 162,420 deaths in 2006. Mesothelioma represents 1.5% of these cases, and small cell lung cancer (SCLC) comprises approximately 20%, with non small cell lung cancer (NSCLC) being responsible for the rest. Lung cancer is characterized by rapid growth and early metastasis. With little progress being made in the development of effective treatments and a poor five-year survival rate, there is a need for new therapeutic approaches. Histone deacetylase inhibitors (HDACI) are a recently developed class of anticancer agents. The acetylated state of histones is associated with transcriptional activity, and active histone acetylation plays a role in re-expression of silenced tumor suppressor genes. Specific HDACI, like LBH589, in vitro induce hyperacetylation of histones, cell cycle arrest and apoptosis. This agent is currently being studied in clinical trials (hematologic malignancies). Our goal was to expand the study of LBH589 to lung cancer. Materials and Methods: In vitro: MTT cell proliferation assays were carried out for 36 cell lines (11 NSCLC cell lines −7 human (h), 4 murine (m)-, 13 SCLC cell lines (h), 12 mesothelioma cell lines −8 h, 4 m- and one human thymoma cell line). IC50 and LD50 were determined and compared to Suberoylanilide hydroxamic acid (SAHA). Also the combination with standard chemotherapy was analyzed. Cell cycle analysis was performed with Flow Cytometry. Conditions tested were LBH589, etoposide and irradiation (IR) alone and in combination. In vivo: Wild type mice and/or SCID mice were injected with tumor cells in the flank (H69, M30, TC1, A549, AE17). When tumors reached 200mm3, LBH589 was administered with daily intraperitoneal (IP) injections (10 and 20mg/kg). Tumors were measured twice weekly. After 2 weeks of therapy tumors were harvested and pharmacokinetic studies were carried out. In addition, SCID mice with H69 tumors were administered etoposide as standard SCLC therapy and combination therapy with LBH. Results: MTT Assay. LBH589 IC50s are significantly lower than SAHA, with values in the low nM range (ranging from 4 to 470nM, median of 20), significantly lower than SAHA. SCLC cell lines were the most sensitive ones, so we decided to pursue the study on this type of lung cancer cell lines. Cell cycle analysis. SCLC cell lines express time-dependent efficacy of LBH589, expressed by an increase in the sub-G1 amount of cells according to the exposure times. Etoposide and IR alone both show modest efficacy in inducing apoptosis, which was increased when adding LBH589. In vivo. LBH589 significantly decreases tumor growth when compared to control in the different cell lines tested. Repeating the experiments in SCID mice yielded the same results, this indicates that there is no immunologic effect related to the effect of LBH589. The effect of HDACI followed by the administration of etoposide was synergistic and statistically significant (p<0.05). Conclusion: HDAI are a recently developed class of anticancer agents, which seem to have promising results on lung cancer cell lines. SCLC cell lines seem to be particularly sensitive to LBH589, an HDAI, with IC50 in the low nM range and efficacy in decreasing tumor size. LBH589 also showed synergy when combined with etoposide. The promising results against SCLC should encourage the design of clinical trials in the search for new therapeutic approaches for this devastating disease.