Poster Presentation 27th Lorne Cancer Conference 2015

Background: Lung cancer is the most common cause of cancer death and non-small cell lung carcinoma (NSCLC) accounts for >80% of cases. Poor survival is driven largely by patients developing metastatic disease, for which current therapies are largely ineffective. The developmental process of epithelial-to-mesenchymal transition (EMT) can be reactivated in cancer, where it can promote cellular invasion and motility. We have shown the EMT-inducer ZEB1 is increased with full malignant transformation of lung epithelial cells and that it drives cellular migration and invasion in NSCLC cell lines in vitro and in vivo. As transcription factors are difficult to therapeutically target we now aim to identify ZEB1 transcriptional targets that may represent better targets to inhibit metastatic capacity of NSCLC cells.  

Results: From seven independent mRNA datasets we have identified a set of candidate ZEB1-upregulated genes in lung cancer. By confirming their expression responds to ZEB1 expression levels and screening these genes with an siRNA-invasion assay we have identified a subset that drive in vitro invasion comparably to ZEB1. Importantly, several of these genes are ‘druggable’ with inhibitors/blocking antibodies available (including PDGFβ, AXL, GAS6, ENPP2, DARC, S100A4, and CD70). We are currently testing the ability of these inhibitors to limit the metastatic capability of NSCLC cell linesto determine their potential as therapies to limit metastasis in NSCLC.

Conclusions: ZEB1 is a significant promoter of metastasis-associated phenotypes in NSCLC cell lines and identification of ZEB1-activated genes, particularly ‘druggable’ genes, may represent novel therapeutic targets for NSCLC.