Metastatic colorectal cancer (mCRC) is a leading cause of cancer death worldwide and the median survival remains poor. The use of novel targeted therapies, such as monoclonal antibody inhibiting the epidermal growth factor receptor (EGFR) offer promise in improving patient outcomes. However, a high proportion of patients with mCRC who receive monoclonal antibody show resistance to such therapy. We hypothesised other biomarkers for resistance to EGFR targeted therapies exist apart from KRAS or BRAF mutation status. Specific aims of this study were to identify resistant and sensitive WT KRAS/WT BRAF colorectal cell lines to anti-EGFR treatment, to identify candidate biomarkers from RNA extracted in resistant colorectal cell line and to validate these findings using qRT-PCR technique. CRC cell lines were tested for resistance/sensitivity to anti-EGFR treatment using the Promega Cell Titer Proliferation Assay. Biomarkers in extracted RNA from the cell lines were determined using Qiagen Human EGFR Pathway Array plates and validated using qRT-PCR. SW48, SNU-C1 and COLO-320DM were resistant to anti-EGFR treatment, with 59.1%, 83.8% and 68.3% cell proliferation respectively while LIM1215, CaCo2 and SW948 were sensitive to the treatment with 18.5%, 42% and 50.3% proliferation respectively (P=0.002). Comparison of resistant versus sensitive cells showed a number of genes to be significantly differentially over-expressed in common, namely HBEGF, EGR1, FN1, AKT3 and MAPK10.