Lung cancer is associated with a high mortality rate, with Non-Small Cell Lung Cancer (NSCLC) accounting for the majority of cases. Mutations in the epidermal growth factor receptor (EGFR) kinase domain have been shown to confer tumourigenic behaviour in NSCLC. At present, there is limited knowledge of lung cancer development and of the mechanism of resistance of these tumours to novel therapeutic approaches using EGFR inhibitors. Genome-wide expression analysis has revealed that cyclin D1 is one of the most strongly down-regulated genes following treatment of H1975 lung tumour cells with an inhibitor of tyrosine kinase. Additionally, nuclear accumulation of β-catenin correlates with the blast crisis phase of CML, which is driven by the oncogenic tyrosine kinase Bcr- Abl. These two observations have led us to hypothesize that oncogenic EGFR mutations trigger tyrosine phosphorylation of β-catenin, thereby inducing the expression of cell cycle regulators such as cyclin D1. To investigate this potential cross-talk between EGFR and Wnt signalling pathways, we used established NSCLC cell lines and also developed a BEAS-2B isogenic cell line to perform a series of gene expression studies. Using this approach, we found that NSCLC cell lines harbouring EGFR mutations express higher levels of active β-catenin in the cytoplasm and nucleus compared to cell lines with wild-type EGFR. This was further verified in the BEAS-2B isogenic cell line. Moreover, mutant EGFR was found to directly activate the Wnt/ β-catenin pathway and this could play a role in the development of resistance to EGFR inhibitors.
|Publication status||Unpublished - 2011|