e14566 Background: We previously demonstrated the synergistic effect of the histone deacetylase inhibitor SNDX-275 and gefitinib in non-small cell lung cancer (NSCLC) cell lines lacking E-cadherin expression. We evaluated the combination effect of SNDX- 275 with erlotinib or lapatinib in lung, head and neck (H&N) and breast cancer cell lines resistant to erlotinib or lapatinib(IC50> 1uM) and expressing Her2. Methods: This study included 10 H&N and 17 NSCLC cell lines, 2 breast cancer cell lines with expressing Her2 (SK BR3, MCF7) and one lacking Her2 expression, MDA-MB231. Cell lines were incubated for 5 days with increasing concentrations (0.16, 1 and 6μM) of SNDX-275, lapatinib and erlotinib alone or in combination. The growth inhibitory effect was analyzed with MTT assay. The combination drug effect was evaluated using CalcuSyn (Cambridge, UK). E-cadherin and Her2 expression was evaluated using microarray analysis and RT-PCR. Her2 was considered positive if the relative expression was >300 by RT-PCR. Protein expression was analyzed with western blots. Results: Among the 17 NSCLC and 10 H&N cell lines 16 (12 NSCLC and 4 H&N) had positive Her2 RNA expression. 2 NSCLC (A549, H1703) and 2 H&N (UMSCC10, UMSCC19) were resistant to erlotinib or lapatinib (IC50>1μM). The 2 breast cancer cell lines 2, MCF7 and MDA-MB-321, were resistant to erlotinib and lapatinib. SNDX-275 increased the expression of E-cadherin in 5 of the 6 cell lines selected (A549, H1703, UMSCC19, MCF7 and MDA- MB-321). Synergistic effect of SNDX-275 1μM and lapatinib 1μM was detected in the MCF7, UMSCC10, UMSCC19 cell lines (Combination Index, CI: 0.09, 0.9, 0.67; respectively), while SNDX-275 1μM and erlotinib 1μM were synergistic in MCF7, MDA-MB-321, H1703 and A549 (CI: 0.2, 0.95, 0.58, 0.32; respectively). Conclusions: The combination of SNDX-275 and erlotinib or lapatinib is active in breast, NSCLC, H&N cell lines resistant to either drug alone. [Table: see text]