By sequencing a panel of 21 genes involved in CRC, we found that, beside KRAS gene, whose previously undetected mutations reached statistical significance as individual gene, the combined mutations of other genes belonging to the EGFR pathway (NRAS, BRAF and PIK3CA) together with mutations at FBXW7 and SMAD4 genes achieved a significant association with resistance to anti-EGFR therapy. This evidence concerns the gene SMAD4 and colorectal carcinoma.