Increased functional expression of voltage-gated sodium (Nav) channels has been reported in a range of cancer cell lines, where it has been linked to cancer cell invasion and increased metastatic potential. However, the cellular mechanisms underlying the regulation of Nav channels in cancer remain unclear. Signalling via the EGF receptor enhances cell proliferation, migration and invasion in many cancer cell types. Moreover, in breast and prostate cancer cells, up-regulation of Nav channel activity has been implicated in the pro-invasive response to EGF stimulation. In this study we have defined the interplay between EGF signalling and Nav channels in non-small cell lung cancer (NSCLC). Using patch clamp electrophysiology, we have shown that tetrodotoxin (TTX)-sensitive Na+ currents are present in a strongly metastatic NSCLC cell line (H460) but absent in a weakly metastatic NSCLC cell line (A549). Crucially, at the resting membrane potential (-27 ± 4 mV, n=12) of the H460 cells, a sustained Na+ current is present, responsible for a small but persistent influx of Na+ into the cells. Treatment of these H460 cells with 100 ng/ml EGF for 12 hours enhanced Na+ current density, whereas treatment with 1 μM gefitinib (an EGFR antagonist) or 10 μg/ml α-EGF function-blocking antibody for 12 hours reduced current density. Similarly, quantitative-PCR and western blot analysis revealed that mRNA and protein levels for the predominant Nav channel α-subunit isoform (Nav1.7) expressed in H460 cells, increased in response to EGF and decreased following inhibition of EGF signalling. Using in vitro bioassays, we demonstrated that whilst EGF enhanced both proliferation and migration of H460 cells by ~40-50%, this effect was independent of Nav channel activity. Importantly, however, EGF enhances H460 cell invasion, and this was found to be at least partly dependent on Nav channel activity. Work is in progress to determine the precise role played by the Nav1.7 isoform in invasive behaviour of NSCLC cells.