Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib
- PMID: 15118073
- DOI: 10.1056/NEJMoa040938
Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib
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.
Copyright 2004 Massachusetts Medical Society
Comment in
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Targeting targeted therapy.N Engl J Med. 2004 May 20;350(21):2191-3. doi: 10.1056/NEJMe048101. Epub 2004 Apr 29. N Engl J Med. 2004. PMID: 15118072 No abstract available.
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EGFR mutations and sensitivity to gefitinib.N Engl J Med. 2004 Sep 16;351(12):1260-1; author reply 1260-1. doi: 10.1056/NEJM200409163511221. N Engl J Med. 2004. PMID: 15371587 No abstract available.
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EGFR mutations and sensitivity to gefitinib.N Engl J Med. 2004 Sep 16;351(12):1260-1; author reply 1260-1. N Engl J Med. 2004. PMID: 15376351 No abstract available.
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EGFR mutations and sensitivity to gefitinib.N Engl J Med. 2004 Sep 16;351(12):1260-1; author reply 1260-1. N Engl J Med. 2004. PMID: 15376352 No abstract available.
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EGFR mutations in non-small cell lung carcinomas may predict response to gefitinib: extension of an emerging paradigm.Adv Anat Pathol. 2005 Mar;12(2):47-52. doi: 10.1097/01.pap.0000155052.68496.e4. Adv Anat Pathol. 2005. PMID: 15731572 No abstract available.
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Lack of mutations in EGFR in gastroenteropancreatic neuroendocrine tumors.N Engl J Med. 2005 Jul 14;353(2):209-10. doi: 10.1056/NEJM200507143530219. N Engl J Med. 2005. PMID: 16014895 No abstract available.
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