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. Anti-epidermal growth factor receptor (anti-EGFR) -targeted therapies have improved the efficacy of conventional chemotherapy in both preclinical and clinical studies (Table I). Although such therapies may lead to partial response or disease stabilisation in some patients, many patients do not benefit from anti-EGFR therapy, and those who do, eventually develop resistance it. Great interest, therefore, exists in elucidating resistance mechanisms for anti-EGFR therapies, as well as those for chemotherapy agents. The molecular mechanisms of resistance to anti-EGFR agents may be attributed to several general processes: (i) resistance due to activation of alternative tyrosine kinase receptors that bypass the EGFR pathway (e.g. c-Met, IGF-1R), (ii) resistance due to increased angiogenesis, (iii) resistance, based on constitutive activation of downstream mediators (e.g. PTEN, K-ras, and others), and (iv) the existence of specific EGFR mutations. Although a large body of preclinical and clinical studies has shed light into the underlying molecular mechanisms for the observed resistance (reviewed in (1)), the lack of validated predictive markers of benefit from anti-EGFR agents may be the result of the complex biology of the EGFR system itself. This complexity arises from the existence of multiple EGFR ligands, a variety of receptor dimerisation partners and the frequent occurrence of receptor cross-talk with members of other receptor families, among other things. Furthermore, it is likely that the biological consequences of EGFR activation vary as a consequence of other mutations present in the tumour. Taking all these factors into consideration, although it has been possible to identify some predictors of clinical benefit (e.g. EGFR overexpression), it may be more fruitful to identify negative predictive factors of benefit to anti-EGFR agents. These factors may be markers that, when present, would render tumours EGFR-independent and therefore not sensitive to EGFR inhibition. Since emerging data from recently published studies have now suggested that a hyperactive mutant K-ras is likely to