Activating Mutations in the Epidermal Growth Factor Receptor Underlying Responsiveness of Non–Small-Cell Lung Cancer to Gefitinib¶
Why this mattered¶
This paper helped turn lung cancer therapy from a largely histology- and chemotherapy-driven field into a genotype-directed one. Gefitinib had produced striking responses in only a minority of patients with non-small-cell lung cancer, and before this study those responses were clinically recognizable but biologically unexplained. Lynch and colleagues showed that many of these exceptional responses were associated with somatic activating mutations in the EGFR kinase domain, especially alterations near the ATP-binding pocket. The key shift was causal and practical: drug sensitivity was not simply a general property of EGFR expression, but could be traced to specific tumor mutations that both activated signaling and made the cancer unusually vulnerable to EGFR inhibition.
After this result, it became newly possible to select patients for treatment based on a molecular lesion rather than treating all patients with the same diagnosis as biologically equivalent. EGFR mutation testing became a model for predictive oncology: identify an oncogenic driver, match it to a targeted inhibitor, and use tumor genotyping to guide therapy. The paper also clarified why early trials of EGFR inhibitors looked inconsistent at the population level while still producing dramatic individual responses. Those responses were not anomalies; they were evidence that lung cancer contained therapeutically distinct molecular subgroups.
Its influence extended well beyond gefitinib. The EGFR story helped establish the modern framework for precision medicine in solid tumors, shaping later work on acquired resistance, including secondary EGFR mutations, and motivating successive generations of EGFR inhibitors. More broadly, it helped normalize the search for actionable driver alterations in lung cancer, a path that later included ALK, ROS1, BRAF, MET, RET, NTRK, and others. The paper mattered because it showed, in a common and lethal cancer, that sequencing a tumor could directly explain drug response and change the logic of clinical treatment.
Abstract¶
BACKGROUND: Most patients with non-small-cell lung cancer have no response to the tyrosine kinase inhibitor gefitinib, which targets the epidermal growth factor receptor (EGFR). However, about 10 percent of patients have a rapid and often dramatic clinical response. The molecular mechanisms underlying sensitivity to gefitinib are unknown. METHODS: We searched for mutations in the EGFR gene in primary tumors from patients with non-small-cell lung cancer who had a response to gefitinib, those who did not have a response, and those who had not been exposed to gefitinib. The functional consequences of identified mutations were evaluated after the mutant proteins were expressed in cultured cells. RESULTS: Somatic mutations were identified in the tyrosine kinase domain of the EGFR gene in eight of nine patients with gefitinib-responsive lung cancer, as compared with none of the seven patients with no response (P<0.001). Mutations were either small, in-frame deletions or amino acid substitutions clustered around the ATP-binding pocket of the tyrosine kinase domain. Similar mutations were detected in tumors from 2 of 25 patients with primary non-small-cell lung cancer who had not been exposed to gefitinib (8 percent). All mutations were heterozygous, and identical mutations were observed in multiple patients, suggesting an additive specific gain of function. In vitro, EGFR mutants demonstrated enhanced tyrosine kinase activity in response to epidermal growth factor and increased sensitivity to inhibition by gefitinib. CONCLUSIONS: A subgroup of patients with non-small-cell lung cancer have specific mutations in the EGFR gene, which correlate with clinical responsiveness to the tyrosine kinase inhibitor gefitinib. These mutations lead to increased growth factor signaling and confer susceptibility to the inhibitor. Screening for such mutations in lung cancers may identify patients who will have a response to gefitinib.
Related¶
- cite → Mutations of the BRAF gene in human cancer — The EGFR lung-cancer mutation paper cites BRAF mutations as precedent that recurrent activating kinase mutations can define oncogene-driven human cancers.