However, in certain tumors (such as CRC) with aberrant genetic alterations, including RAS [110], BRAF [69], PIK3CA [111], EGFR S492R mutations [112], PTEN loss [113], and STAT3 phosphorylation [114] confer insensitivity to anti-EGFR therapy through constitutive activation of EGFR downstream signaling cascades regardless of EGFR blockade (Figure 3C). This evidence concerns the gene STAT3 and colorectal carcinoma.