April 2016 Abstracts, ELCC 2016 – Tumour biology and pathology S63 cells. Prognoscan assessment identified decrease SASH1 mRNA expression lead to a prognostic reduction in patient survival. The depletion of SASH1 in lung cells resulted in a significant increase in cellular proliferation in cancer lung cells. Connectivity mapping predicted the drug Chloropyramine would lead to an increase in SASH1 expression. We demonstrated that Chloropyramine upreg- ulates SASH1 in malignant cell lines. In keeping with this we have demonstrated that Chloropyramine inhibited lung cancer prolifer- ation in vitro. These novel observations support the tumour sup- pressive role of SASH1 in lung tumourgenesis. Further work is on- going to understand the function of SASH1 in lung cancer growth. Conclusions: The upregulation of SASH1, either by chemical agents or gene therapy, is a potential novel approach to the management of lung cancer and other solid tumours. Legal entity responsible for the study: Queensland University of Technology Funding: Queensland Health Disclosure: All authors have declared no conflicts of interest. 17P Examination of EXOSC4 as a new prognostic marker and a novel therapeutic avenue in lung adenocarcinoma K. O’Byrne, N. Paquet, J.K. Box, M. Adams, D. Richard. Institute of Health and Biomedical Innovation, Cancer and Ageing Research Program, Queensland University of Technology, Brisbane, Australia Background: Although prevention and early detection of the disease greatly improved over the past few years, lung cancer remains the leading cause of cancer deaths. In order to be able to treat a larger population, we are in urgent need for novel treat- ments. While it is known that DNA repair genes play a major role in the oncogenic transformation, they also represent a weakness of cancers that constitute a therapeutic opportunity. To identify novel DNA repair genes implicated in Lung cancers, we conducted an in silico investigation to identify genes co-regulated with two DNA repair factors, BRCA2 and hSSB1. This approach allowed for the identification of EXOSC4, a component of the RNA Exosome machinery, as a potential factor involved in the maintenance of genome stability and that is deregulated in lung cancer. Methods: We performed a detailed genomic analysis of EXOSC4 in lung cancers from The Cancer Genome Atlas project, including DNA copy number alteration (CNA), RNA expression analyses. Association between EXOSC4 expression and patient survival was determined with the Kaplan–Meier log-rank. Multiple cell lines were investigated for EXOSC4 levels by RT-PCR and western blots. Deregulation of EXOSC4 by knockdown was used to delineate the function of EXOSC4 in cancer progression. Ex vivo functional studies including cell proliferation and viability assays were performed on cell lines. Results: Significant copy number alteration was found in lung cancer, and was shown to correlate with EXOSC4 transcripts accumulation when compared with normal tissues. Over- expression of EXOSC4 is significantly associated with poor cancer survival in adenocarcinoma (HR = 1.9, logrank P = 8e -8 ) but not in SCLC. Preliminary results obtain from qRT-PCR and Western blot analysis confirmed that EXOSC4 accumulates in cancer cells when compared to immortalized lung epithelial cells. First results indicate that EXOSC4 knock down in these cells is associated with a significant reduction in cells proliferation. Our preliminary results indicated that cell survival is not significantly impacted by EXOSC4 depletion. Conclusions: These results provide an insight into EXOSC4 deregulation in lung cancer and suggest that EXOSC4 expression is necessary for cancer progression. Legal entity responsible for the study: Queensland University of Technology Funding: Queensland Health Disclosure: All authors have declared no conflicts of interest. 18P Epithelial-to-mesenchymal transition (EMT) is required for resistance to anti-folate chemotherapy in lung cancer S. Liang 1 , T.M. Marti 1 , P. Dorn 1 , L. Froment 1 , S. Hall 1 , S. Berezowska 2 , G. Kocher 1 , R.A. Schmid 1 , R. Peng 1 . 1 Division of Thoracic Surgery, Inselspital Bern, Bern, Switzerland , 2 Institute of Pathology, University of Bern, Bern, Switzerland Background: Lung cancer is the leading cause of cancer lethality worldwide and non-small cell lung cancer (NSCLC) accounts for about 80% of all lung cancer cases. Although multiple therapeutic options have been developed, chemotherapy remains the first- line treatment for patients with advanced NSCLC. However, the effectiveness of chemotherapy is often limited by drug resistance and the molecular mechanisms underlying drug resistance are still poorly understood. Methods: In this study, we investigated the cells and the underlying mechanisms that confer NSCLC resistance to chemotherapeutic agent Pemetrexed (MTA). MTA resistant cells, generated by chronical exposure to MTA of both NSCLC cell lines and primary tumor cells, were phenotypically and functionally characterized. Results: MTA-resistant NSCLC cells featured an activated EMT, as manifested by significant upregulation of EMT-related factors. In addition, an experimentally induced EMT, by treatment with TGFb, rendered the otherwise non-resistant NSCLC cells to be refractory to MTA. In concord, pharmacological inhibition of EMT overcomes NSCLC resistance to MTA. The same principle holds true with primary NSCLC cells. Thus, EMT is required for NSCLC resistance to anti-folate chemotherapy and blocking EMT constitutes a promising avenue to enhance the efficacy of MTA- based chemotherapy. Conclusions: EMT accounts for resistance to anti-folate chemotherapy in NSCLC and blocking EMT overcomes the resistance phenomenon. Legal entity responsible for the study: Shunqing Liang Funding: Inselspital Disclosure: All authors have declared no conflicts of interest. 19P Comparative effectiveness analysis of HSP90 inhibitors in non-small cell lung cancer A. Marrugal 1 , L. Ojeda M ´ arquez 1 , Á. Quintanal 2 , S. Molina-Pinelo 2 , I. Ferrer 1 , A. Carnero 3 , L. Paz-Ares 2 . 1 Molecular Oncology and Novel Therapies, Hospital Universitario Virgen del Rocio, Seville, Spain , 2 Molecular Oncology and Novel Therapies, University Hospital 12 de Octubre, Madrid, Spain, 3 Cancer Molecular Biology, Hospital Universitario Virgen del Rocio, Seville, Spain Background: Heat Shock Protein-90 (HSP90) over-expression has been related to poor prognosis in cancer. The role of this chaperone in malignancy is mediated by its ability to control the stabilization of known oncogenic client proteins. Therefore, the inhibition of HSP90 is a promising treatment strategy. One of the best response rates for HSP90 inhibition has been reported in non-small cell lung cancer (NSCLC). Nevertheless, the characterization of its efficacy in some molecularly defined subgroups will be key for successful clinical development. Methods: Different human NSCLC cell lines carrying gene mutations whose relationship with HSP90 has been reported