Kobayashi S et al. (2005) EGFR mutation and resistance of non–small-cell lung cancer to gefitinib. New Engl J Med 352: 786–792

A recent report by Kobayashi et al. sheds light on the mechanism of drug resistance in non-small-cell lung cancer patients who are initially responsive to anilinoquinazoline epidermal growth factor receptor (EGFR) inhibitors.

These drugs—namely gefitinib and erlotinib—are used for second-line or third-line therapy in patients with metastatic disease, and work by targeting the EGFR pathway. The majority of highly responsive tumors bear activating mutations of the EGFR gene. All patients appear to relapse eventually, however, and Kobayashi and colleagues hypothesized that this might be due to further somatic EGFR mutations.

They describe the case of a 71-year-old patient with advanced non-small-cell lung cancer who had a clinical and radiographic response to gefitinib after failing chemotherapy. After two years of complete remission, however, the patient relapsed and has since been treated with salvage therapies for advanced lung cancer.

Using genomic DNA extracted from a tumor specimen from the patient, the tyrosine kinase domain of the EGFR gene was sequenced and the results compared with those from the first biopsy. This revealed a second EGFR mutation—a novel C→T transition in exon 20—which resulted in a threonine-to-methionine substitution at position 790 of the protein. In vitro analysis demonstrated that this mutation, named T790M, conferred gefitinib resistance, and structural modeling work predicted that it would cause steric hindrance of gefitinib binding.

Together with results from patients with gastrointestinal stromal tumors and chronic myeloid leukemia, these findings show that somatic mutations in EGFR are likely to be responsible for relapses in patients who are at first responsive to gefitinib or erlotinib. Kobayashi et al. advise, therefore, that it might be appropriate to incorporate repeated biopsies into clinical studies in this area. They also note that results from a biochemical screen of alternative EGFR inhibitors identified a compound (CL-387,785) that appeared to overcome resistance rendered by the T790M mutation. The characterization of resistance mutations might, therefore, pave the way for the development of effective second-generation EGFR inhibitors.