Ras mutational status is a biomarker for resistance to EGFR inhibitors in colorectal carcinoma.

The epidermal growth factor receptor (EGFR) has been validated as a therapeutic target in several human tumours, including colorectal cancer (CRC). Although EGFR expression is used for patient selection, clinical experience shows that levels of EGFR expression (measured by immunohistochemistry) do not predict clinical benefit. Ras mutations in codons 12, 13 and 61 (found in 40-45% of CRC cases) result in inhibition of GTPase activity, thus leading to the constitutive activation of the ras proteins, which may render tumour cells independent of EGFR signalling and thereby, resistant to cetuximab, panitumumab and EGFR TKIs. Data from several recently published studies, as reviewed in this article, in patients with metastatic CRC (OPUS, CRYSTAL) clearly indicated that benefit from cetuximab, when added to chemotherapy, was only restricted to patients with wild-type K-ras tumours. These results showed that K-ras mutations predict the lack of clinical benefit from cetuximab and panitumumab therapies in CRC and indicate that K-ras status should be considered when selecting CRC patients as candidates for these antibodies. Moreover, the results from these studies should also trigger retrospective analyses of K-ras mutations from all available trials in CRC (as well as non-small cell lung cancer and pancreatic cancer). These studies may enable further establishment of the correlation between K-ras mutations and resistance to cetuximab and panitumumab in CRC patients.