Pao W et al. (2005) KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Medicine 2: 57–61

Sensitivity to the small-molecule tyrosine-kinase inhibitors gefitinib and erlotinib is associated with mutations in the EGFR gene. A recent study by Pao and colleagues has shown that mutations in KRAS, a member of the RAS family, appear to be linked to a lack of sensitivity to these drugs.

Sixty lung adenocarcinomas that were known to be sensitive or refractory to single-agent gefitinib or erlotinib were analyzed. Each tumor specimen was screened for mutations in EGFR exons 18–21 and KRAS exon 2, and mutation status was then compared with sensitivity to the two drugs.

KRAS mutations were found in 9 (24%) of 38 tumors that were refractory to gefitinib or erlotinib, whereas none of these tumors bore EGFR mutations. Of 22 tumors sensitive to either drug, no KRAS mutations were found in the 21 specimens examined, but 17 (77%) of 22 tumors bore EGFR mutations.

How to treat tumors with neither EGFR nor KRAS mutations is still unclear. These data suggest, however, that KRAS mutations might predict a lack of response to gefitinib or erlotinib in patients with lung adenocarcinoma. Pao et al. conclude that it might be helpful to establish the mutational status of both EGFR and KRAS when making treatment decisions in this setting, and they recommend that this be studied further in large, prospective trials.